Piperazine oxytocin receptor antagonists

ABSTRACT

This invention relates to certain novel piperazine compounds and derivatives thereof, their synthesis, and their use as oxytocin receptor antagonists. One application of these compounds is in the treatment of preterm labor in mammals, especially humans. The ability of the compounds to relax uterine contractions in mammals also makes them useful for treating dysmenorrhea and stopping labor prior to cesarean delivery.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present invention is related to U.S. provisional application Ser.No. 60/050,132 filed Jun. 18, 1997, the contents of which are herebyincorporated by reference.

STATEMENT REGARDING FEDERALLY-SPONSORED R&D

Not Applicable

REFERENCE TO MICROFICHE APPENDIX

Not Applicable

FIELD OF THE INVENTION

The present invention provides novel compounds, novel compositions,methods of their use and methods of their manufacture; such compoundsare generally pharmacologically useful as agents in obstetric andgynecologic therapy in mammals. More specifically, the compounds of thepresent invention are useful in the treatment of preterm labor,dysmenorrhea and for stopping labor preparatory (i.e., prior) tocaesarean delivery.

BACKGROUND OF THE INVENTION

In the field of obstetrics, one of the most important problems is themanagement of preterm labor. A significant number of the pregnanciesprogressing past 20 weeks of gestation experience premature labor anddelivery, which is a leading cause of neonatal morbidity and mortality.Despite major advances in neonatal care, retention of the fetus in uterois preferred in most instances.

Tocolytic (uterine-relaxing) agents that are currently in use include β₂-adrenergic agonists, magnesium sulfate and ethanol. Ritodrine, theleading β₂ -adrenergic agonist, causes a number of cardiovascular andmetabolic side effects in the mother, including tachycardia, increasedrenin secretion, hyperglycemia (and reactive hypoglycemia in theinfant). Other β₂ -adrenergic agonists, including terbutaline andalbuterol have side effects similar to those of ritodrine. Magnesiumsulfate at plasma concentrations above the therapeutic range of 4 to 8mg/dL can cause inhibition of cardiac conduction and neuromusculartransmission, respiratory depression and cardiac arrest, thus makingthis agent unsuitable when renal function is impaired. Ethanol is aseffective as ritodrine in preventing premature labor, but it does notproduce a corresponding reduction in the incidence of fetal respiratorydistress that administration of ritodrine does.

It has been proposed that an oxytocin antagonist would be the idealtocolytic agent. In the last few years, evidence has accumulated tostrongly suggest that the hormone oxytocin may be a physiologicalinitiator of labor in several mammalian species including humans.Oxytocin is believed to exert this effect in part by directlycontracting the uterine myometrium and in part by enhancing thesynthesis and release of contractile prostaglandins from the uterineendometrium/decidua. These prostaglandins may, in addition, be importantin the cervical ripening process. By these mechanisms, the process oflabor (term and preterm) is initiated by a heightened sensitivity of theuterus to oxytocin, resulting in part as a result of a well-documentedincrease in the number of oxytocin receptors in this tissue. This"up-regulation" of oxytocin receptors and enhanced uterine sensitivityappears to be due to trophic effects of rising plasma levels of estrogentowards term. By blocking oxytocin, one would block both the direct(contractile) and indirect (enhanced prostaglandin synthesis) effects ofoxytocin on the uterus. An oxytocin blocker, or antagonist, would likelybe more efficacious for treating preterm labor than current regimens. Inaddition, since oxytocin at term has major effects only on the uterus,such an oxytocin antagonizing compound would be expected to have few, ifany, side effects.

The compounds of the present invention are also useful in the treatmentof dysmenorrhea. This condition is characterized by cyclic painassociated with menses during ovulatory cycles. The pain is thought toresult from uterine contractions and ischemia, probably mediated by theeffect of prostaglandins produced in the secretory endometrium. Byblocking both the direct and indirect effects of oxytocin on the uterus,an oxytocin antagonist is more efficacious for treating dysmenorrheathan current regimens. An additional use for the present invention isfor the stoppage of labor preparatory to cesarean delivery.

It is, therefore, a purpose of this invention to provide substanceswhich more effectively antagonize the function of oxytocin in diseasestates in animals, preferably mammals, especially in humans. It isanother purpose of this invention to provide a method of antagonizingthe functions of oxytocin in disease states in mammals. It is also apurpose of this invention to develop a method of preventing or treatingthe oxytocin-related disorders of preterm labor and dysmenorrhea byantagonizing the binding of oxytocin to its receptor.

It has now been found that compounds of the present invention areantagonists of oxytocin and bind to the oxytocin receptor. When theoxytocin receptor is bound by the compounds of the present invention,oxytocin is antagonized by being blocked from its receptor and thusbeing unable to exert its biologic or pharmacologic effects. Thecompounds of the present invention are therefore useful in the treatmentand prevention of oxytocin-related disorders of animals, preferablymammals and especially humans. These disorders are primarily pretermlabor and dysmenorrhea. The compounds are also useful for stoppage oflabor preparatory to cesarean delivery.

SUMMARY OF THE INVENTION

The compounds of the present invention are of the formula ##STR1##wherein: Ar is unsubstituted, mono- or disubstituted phenyl, naphthyl,pyridyl, pyrazinyl or pyrimidinyl, in which the substituents on carbonare independently selected from the group consisting of: C₁₋₅ alkyl,C₁₋₅ alkoxyl, halogen, nitro, cyano, and CF₃ ;

R¹ is H, CON(R⁴)₂ ;

R² is CF₃, OCF₃, or OCH₂ CF₃ ;

R³ is independently selected from the group consisting of: H, halogen,CF₃, OR⁵, NHR⁶, and Het;

R⁴ is independently selected from the group consisting of: hydrogen andC₁₋₅ alkyl;

R⁵ and R⁶ are independently selected from the group consisting of:hydrogen; C₁₋₅ alkyl; mono- or poly-halogenated C₁₋₅ alkyl; substitutedC₁₋₅ alkyl wherein the substituent is selected from carboxy, CO₂ -C₁₋₅alkyl, CON(R⁴)₂, or morpholinyl; S-C₁₋₅ alkyl; SO-C₁₋₅ alkyl; SO₂ -C₁₋₅alkyl; CN; carboxy; CO-C₁₋₅ alkyl; CON(R⁴)₂ ; pyridinyloxy;pyridinyloxy-N-oxide; triazolyl; tetrazolyl; morpholinyl; unsubstitutedor substituted phenoxy wherein the phenoxy is substituted with one tothree substituents independently selected from C₁₋₅ alkyl, halogen, CF₃or CN; ##STR2## wherein R⁷ is selected from hydrogen, C₁₋₅ alkyl, C₃₋₇cycloalkyl substituted C₁₋₅ alkyl, mono or polyhalogenated C₁₋₅ alkyl,mono or polyhalogenated C₁₋₅ alkyloxycarbonyl, hydroxy C₁₋₅ alkyl, CO₂-C₁₋₅ alkyl, CON(R⁴)₂, CO-C₁₋₅ alkyl, SO₂ -C₁₋₅ alkyl or ##STR3## Het isselected from pyridinyl, imidazolyl, triazolyl and morpholinyl; and n isan integer from 1 to 2; and pharmaceutically acceptable salts thereof.

Further embodiments of the invention include compounds of Structure Iwherein:

R⁵ is ##STR4## where R⁷ is selected from the group consisting of:hydrogen, C₃₋₇ cycloalkyl substituted C₁₋₅ alkyl, SO₂ -C₁₋₅ alkyl,CO-C₁₋₅ alkyl, hydroxy C₁₋₅ alkyl;

R⁶ is hydrogen, benzimidazolylcarbonyl, or CO-C₁₋₅ alkyl; and

Het is triazolyl; and pharmaceutically acceptable salts thereof.

Still further embodiments include compounds of Structure I wherein

Ar is mono-C₁₋₅ alkylsubstituted phenyl;

R¹ is CONH₂ ;

R² is OCH₂ CF₃ ; and

R³ is ##STR5##

Even further embodiments are compounds of the Structure II: ##STR6##where R² and R⁷ are defined above.

Representative compounds of the invention are the following:

1-(4-(4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;

1-(4-(N-cyclopropylmethyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;

1-(4-(N-methylsulfonyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;

1-(4-(N-acetyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenyl-acetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;

1-(4-(N-2-methyl-2-hydroxypropyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)-piperazine;

1-(4-amino-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;

1-(4-(5-benzimidazolylcarbonylamino)-2-(2,2,2-trifluoroethoxy)-phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;

1-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methyl-phenyl)piperazine;

1-(2-trifluoromethylphenylacetyl)-2-carbamoyl-4-(2-methylphenyl)-piperazine;

1-(2-trifluoromethoxyphenylacetyl)-2-carbamoyl-4-(2-methylphenyl)-piperazine;

1-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-4-(2-cyanophenyl)piperazine;

1-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-4-(2-methoxyphenyl)-piperazine;

1-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-4-(2-chlorophenyl)piperazine;

1-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-4-(2-pyridyl)piperazine;

1-(4-acetylamino-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;

1-(4-chloro-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;

1-(5-chloro-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;

1-(4-trifluoromethyl-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;

1-(5-trifluoromethyl-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;

1-(4-(2-pyridinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;

1-(3-chloro-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;

1-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-4-(3-trifluoromethylphenyl)-piperazine;

1-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-4-(2-pyrazinyl)piperazine

1-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-4-(2-pyrimidinyl)piperazine

1-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-4-(2,6-dimethylphenyl)-piperazine

1-(4-(1-triazolyl)-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;

1-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-4-(4-fluorophenyl)piperazine

1-(4-fluoro-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;

1-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-4-(2-naphthyl)piperazine

1-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-N-methylcarbamoyl-4-(2-methylphenyl)piperazine;

1-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-N-ethylcarbamoyl-4-(2-methylphenyl)piperazine;

1-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-N,N-dimethylcarbamoyl-4-(2-methylphenyl)piperazine;

1-(4-(4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;

1-(4-(N-acetyl-4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;and

1-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-4-(3-ethylphenyl)piperazine,and pharmaceutically acceptable salts thereof.

A preferred class of compounds of the invention are the following:

1-(4-(4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;

1-(4-(N-cyclopropylmethyl-4-piperidinyloxy)-2-(2,2,2,-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;

1-(4-(N-methylsulfonyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)-phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;

1-(4-(N-acetyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenyl-acetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;

1-(4-(N-2-methyl-2-hydroxypropyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetly)-2-carbamoyl-4-(2-methylphenyl)-piperazine.

1-(4-acetylamino-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;

1-(4-(1-triazolyl)-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;

1-(2-(2,2,2,-trifluoroethoxy)phenylacetyl)-4-(2-naphthyl)piperazine;

1-(4-(4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;

1-(4-(N-acetyl-4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;and pharmaceutically acceptable salts thereof.

Illustrating the invention is a pharmaceutical composition comprisingany of the compounds described above and a pharmaceutically acceptablecarrier. An example of the invention is a pharmaceutical compositionmade by combining any of the compounds described above and apharmaceutically acceptable carrier. An illustration of the invention isa process for making a pharmaceutical composition comprising combiningany of the compounds described above and a pharmaceutically acceptablecarrier.

Further illustrating the invention is a method of eliciting an oxytocinantagonizing effect in a mammal in need thereof, comprisingadministering to the mammal a therapeutically effective amount of any ofthe compounds or pharmaceutical compositions described above to elicitan oxytocin antagonizing effect.

An example of the invention are methods of treating preterm labor,preventing preterm labor, stopping preterm labor, stopping laborpreparatory to cesarian delivery, and/or treating dysmenorrhea in amammal in need thereof, comprising administering to the mammal atherapeutically effective amount of any of the compounds orpharmaceutical compositions described above.

Further exemplifying the invention is the use of any of the compoundsdescribed above in the preparation of a medicament for the treatment ofpreterm labor, dysmenorrhea and/or stoppage of labor prior to cesariandelivery in a mammal in need thereof.

More particularly illustrating the invention is a drug which is usefulfor treating preterm labor, dysmenorrhea and/or stopping labor prior tocesarian delivery in a mammal in need thereof, the effective ingredientof the said drug being any of the compounds descibed above.

More specifically exemplifying the invention are methods of increasingfertility and embryonic survival in a farm animal in need thereof,and/or controlling the timing of estrus in a farm animal in needthereof, comprising administering to the farm animal a therapeuticallyeffective amount of any of the compounds or pharmaceutical compositionsdescribed above.

Another example of the invention is a method for improving survival of afarm animal neonate comprising controlling timing of parturition toeffect delivery of the neonate during daylight hours by administering toa farm animal which is expected to deliver the neonate within 24 hours atherapeutically effective amount of any of the compounds orpharmaceutical compositions described above.

Additional illustrations of the instant invention are methods ofantagonizing vasopressin from binding to its receptor site, inducingvasodilation, treating hypertension, inducing diuresis and/or inhibitingplatelet agglutination in a mammal in need thereof comprising the stepof administering to the mammal a therapeutically effective amount of anyof the compounds or pharmaceutical compositions described above.

BRIEF DESCRIPTION OF THE DRAWINGS

Not Applicable

DETAILED DESCRIPTION OF THE INVENTION

Representative compounds of the present invention are oxytocinantagonists which display submicromolar affinity for the human oxytocinreceptor. Compounds of this invention were found to have IC₅₀ values forthe human oxytocin receptor in the range of 1-500 nM.

The compounds of the present invention are administered in dosageseffective to antagonize the oxytocin receptor where such treatment isneeded, as in the treatment of preterm labor. For use in medicine, thesalts of the compounds of this invention refer to non-toxic"pharmaceutically acceptable salts." Other salts may, however, be usefulin the preparation of the compounds according to the invention or oftheir pharmaceutically acceptable salts. Salts encompassed within theterm "pharmaceutically acceptable salts" refer to non-toxic salts of thecompounds of this invention which are generally prepared by reacting thefree base with a suitable organic or inorganic acid. Representativesalts include the following:

Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate,Borate, Bromide, Calcium, Camsylate, Carbonate, Chloride, Clavulanate,Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate,Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate,Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride,Hydroxynaphthoate, Iodide, Isothionate, Lactate, Lactobionate, Laurate,Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate,Methylsulfate, Mucate, Napsylate, Nitrate, N-methylglucamine ammoniumsalt, Oleate, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate,Phosphate/diphosphate, Polygalacturonate, Salicylate, Stearate, Sulfate,Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate,Triethiodide and Valerate. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g. sodium or potassiumsalts; alkaline earth metal salts, e.g. calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g. quaternary ammoniumsalts.

The compounds of the present invention, may have chiral centers andoccur as racemates, racemic mixtures and as individual diastereomers, orenantiomers with all isomeric forms being included in the presentinvention. Therefore, where a compound is chiral, the separateenantiomers, substantially free of the other, are included within thescope of the invention; further included are all mixtures of the twoenantiomers. Also included within the scope of the invention arepolymorphs and hydrates of the compounds of the instant invention.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds of this invention which arereadily convertible in vivo into the required compound. Thus, in themethods of treatment of the present invention, the term "administering"shall encompass the treatment of the various conditions described withthe compound specifically disclosed or with a compound which is notspecifically disclosed, but which converts to the specified compound invivo after administration to the patient. Conventional procedures forthe selection and preparation of suitable prodrug derivatives aredescribed, for example, in "Design of Prodrugs," ed. H. Bundgaard,Elsevier, 1985. Metabolites of these compounds include active speciesproduced upon introduction of compounds of this invention into thebiological milieu.

The term "therapeutically effective amount" shall mean that amount of adrug or pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought by aresearcher or clinician.

The term "alkyl" or "Alk" shall mean straight or branched chain alkanesof one to five total carbon atoms, or any number within this range(i.e., methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl,tert-butyl, etc.).

The term "alkoxy," as used herein, refers to straight or branched chainalkoxides of the number of carbon atoms specified (e.g., C₁₋₅ alkoxy),or any number within this range (i.e., methoxy, ethoxy, etc.).

The term "halogen" shall include iodine, bromine, chlorine and fluorine.

The terms "mono- or polyhalogenated C₁₋₅ alkyl," "mono- orpolyhalogenated C₁₋₅ alkoxy," "mono- or polyhalogenated C₁₋₅ alkenyl,""mono- or polyhalogenated C₁₋₅ alkynyl" and "mono- or polyhalogenatedC₁₋₅ hydroxyalkyl," as used herein, include both straight and branchedchain C₁₋₅ alkanes, alkoxides, alkenes, alkynes or hydroxyalkaneswherein one or more of the hydrogen atoms on the alkyl, alkoxy, alkenyl,alkynyl or hydroxyalkyl chain is replaced with a halogen atom (e.g.,CF₃, OCF₃, OCH₂ CF₃).

The term "substituted" shall be deemed to include multiple degrees ofsubstitution by a named substitutent.

Where multiple substituent moieties are disclosed or claimed, thesubstituted compound can be independently substituted by one or more ofthe disclosed or claimed substituent moieties, singly or plurally.

The term "preterm labor" shall mean expulsion from the uterus of aviable infant before the normal end of gestation, or more particularly,onset of labor with effacement and dilation of the cervix before the37th week of gestation. It may or may not be associated with vaginalbleeding or rupture of the membranes.

The term "dysmenorrhea" shall mean painful menstruation.

The term "cesarean delivery" shall mean incision through the abdominaland uterine walls for delivery of a fetus.

As used herein, the term "composition" is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The ability of the compounds of the present invention to antagonizeoxytocin makes these compounds useful as pharmacologic agents formammals, especially for humans, for the treatment and prevention ofdisorders wherein oxytocin may be involved. Examples of such disordersinclude preterm labor and dysmenorrhea. These compounds may also findusefulness for stoppage of labor preparatory to cesarean delivery.Additionally, such compounds are useful in inducing contraception inmammals inasmuch as oxytocin antagonists have now been shown to inhibitthe release of oxytocin-stimulated luteinizing hormone (LH) by anteriorpituitary cells.

The present invention is also directed to combinations of the compoundsof the present invention with one or more agents useful in the treatmentof disorders such as preterm labor, dysmenorrhea and stopping laborprior to cesarean delivery. More specifically, the compounds of theinstant invention may be effectively administered in combination witheffective amounts of other tocolytic agents used in the treatment ofpreterm labor such as β-adrenergic agonists (e.g., ritodrine,isoproterenol, terbutaline, albuterol), magnesium sulfate, ethanol,other oxytocin antagonists (e.g., atosiban), calcium transport blockers(e.g., nicardipine, nifedipine), prostaglandin synthesis inhibitors(e.g., indomethacin), nitric oxide donors (e.g., nitroglycerine,S-nitroso-N-acetylpenicillamine), phosphodiesterase inhibitors, andprogestins (e.g., progesterone). Preferred combinations are simultaneousor alternating treatments of an oxytocin receptor antagonist of thepresent invention and a second tocolytic agent. In accordance with themethod of the present invention, the individual components of thecombination can be administered separately at different times during thecourse of therapy or concurrently in divided or single combinationforms. The instant invention is therefore to be understood as embracingall such regimes of simultaneous or alternating treatment and the term"administering" is to be interpreted accordingly. The compounds of theinstant invention may also be used in combination with antenatalsteroids (e.g., dexamethasone). This particular combination hasbeneficial effects on the neonate by both decreasing uterine activity toprolong gestation and increasing fetal maturation. It will be understoodthat the scope of combinations of the compounds of this invention withother agents useful for treating oxytocin related conditions includes inprinciple any combination with any pharmaceutical composition useful fortreating preterm labor, dysmenorrhea or stopping labor prior to cesareandelivery.

The oxytocin antagonist compounds of the present invention are alsouseful for improving reproductive efficiency in farm animals. In certainfarm animals (e.g., sheep, cattle, swine, horses and goats), thebeginning of the estrous cycle is typically marked by behavioral estruswhen the female animal accepts the male for mating. Ovulation of theovarian follicle occurs shortly after onset of estrus and cells in thefollicle give rise to the corpus luteum. The cells that form the corpusluteum produce progesterone and they also produce oxytocin. Thesecretion of oxytocin from the corpus luteum and/or pituitary acts onthe uterine endometrium to stimulate the secretion of prostaglandins (inparticular PGF) which, in turn, causes the regression of the corpusluteum of the ovary. PGF is, therefore, the luteolytic hormone. In thecycling animal (i.e., where mating and fertilization have not occurred),destruction of the corpus luteum removes the source of progesteronewhich is key to the preparation of the uterus for pregnancy. Thepresence of a viable conceptus (i.e., the embryo and its associatedmembranes) is necessary to prevent the luteolytic process. In fact, thefirst key signal that the conceptus must produce is the one to preventregression of the corpus luteum (i.e., the maternal recognition ofpregnancy signal). Thus, in the animal where mating and fertilizationhave occurred, the conceptus secretes a factor that antagonizes theaction of oxytocin to induce luteolysis. This results in maintenance ofa functioning corpus luteum and the continued secretion of progesteronewhich is obligatory to the initiation of pregnancy.

Administration of an oxytocin antagonist of the present invention atthis critical period after fertilization (i.e., just prior to or duringthe period of maternal recognition of pregnancy) supplements the naturalsignal from the conceptus (i.e., maternal recognition of pregnancy) toprolong corpus luteal function. The result is to increase pregnancyrates by enhancing the chances of impregnation through a reduction inembryonic loss. Thus, to improve fertility and embryonic survival in afarm animal, a mated animal, for example, a mated ewe, is treated withan oxytocin antagonist compound beginning on between day 10 to day 15after onset of estrus. The oxytocin antagonist compound is administeredto the mated animal for a period of one day to three weeks, preferablyone week to three weeks, most preferably one week to two weeks.

The compounds of the present invention are also useful for controllingthe timing of parturition in farm animals so that delivery of theneonates occurs during the daytime. Approximately 80% of livestock aredelivered at night and up to 5 to 10% of newborns die because thedeliveries are not monitored properly. An oxytocin antagonist compoundof the present invention administered to the mother on the eveningbefore expected delivery delays parturition so that the delivery occursduring the daylight hours. By delaying the timing of parturition, propermonitoring of the delivery and the neonates is ensured, resulting inincreased survival rates of the newborns.

In addition, the oxytocin antagonists of the instant invention can alsobe used to control the timing of estrus in a cycling farm animal bypreventing luteal regression. An oxytocin antagonist compound of theinstant invention is administered to a cycling farm animal prior toexpected estrus to prevent regression of the corpus luteum. Dailyadministration of the compound retards estrus until administration ofthe compound ceases. Preferably, the oxytocin antagonist compound isadministered at least 1 day prior to expected estrus. By delaying estrusin a group of farm animals, a farmer can synchronize estrus among thegroup to provide time and cost savings in farm management.

The compounds of the present invention also bind to the vasopressinreceptor and are therefore useful as vasopressin antagonists.Vasopressin antagonists are useful in the treatment or prevention ofdisease states involving vasopressin disorders; thus, the compounds areuseful for inducing vasodilation, treating hypertension, inducingdiuresis, inhibiting platelet agglutination and treating congestiveheart failure.

The compounds of the present invention can be administered in such oraldosage forms as tablets, capsules (each including timed release andsustained release formulations), pills, powders, granules, elixers,tinctures, suspensions, syrups and emulsions. Likewise, they may also beadministered in intravenous (both bolus and infusion), intraperitoneal,subcutaneous or intramuscular form, all using forms well known to thoseof ordinary skill in the pharmaceutical arts. An effective but non-toxicamount of the compound desired can be employed as a tocolytic agent.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound or salt thereof employed. An ordinarily skilled physician,veterinarian or clinician can readily determine and prescribe theeffective amount of the drug required to prevent, counter or arrest theprogress of the condition.

Oral dosages of the present invention, when used for the indicatedeffects, will range between about 0.0025 to 5.0 gm/day orally. Moreparticularly, when administered orally for the treatment of pretermlabor, an effective daily dose will be in the range of 0.005 mg/kg toabout 100 mg/kg of body weight, preferably, from 0.01mg/kg to 50 mg/kg,most preferably from 0.1 mg/kg to 50 mg/kg, administered in single ordivided dose. For oral administration, the compositions are preferablyprovided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0,2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the patientto be treated. A medicament typically contains from about 0.01 mg toabout 500 mg of the active ingredient, preferably, from about 1 mg toabout 100 mg of active ingredient. Intravenously, the most preferreddoses will range from 0.1 to about 10 mg/minute during a constant rateinfusion. Advantageously, compounds of the present invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three or four times daily.Furthermore, preferred compounds for the present invention can beadministered in intranasal form via topical use of suitable intranasalvehicles, or via transdermal routes, using those forms of transdermalskin patches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittantthroughout the dosage regimen.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient, and are typically administeredin admixture with suitable pharmaceutical diluents, excipients orcarriers (collectively referred to herein as "carrier" materials)suitably selected with respect to the intended form of administration,that is, oral tablets, capsules, elixirs, syrups and the like, andconsistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, carboxymethylcellulose, polyethylene glycol, waxes andthe like. Lubricants used in these dosage forms include sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and the like. Disintegrators include, withoutlimitation, starch, methyl cellulose, agar, bentonite, zanthan gum andthe like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethyl-aspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Abbreviations used in the instant specification, particularly theSchemes and Examples, are as follows:

AIBN=azo bis(isobutyronitrile)

Bn=benzyl

Boc=t-butyloxycarbonyl

BOP=benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate

DCC=1,3-dicyclohexylcarbodiimide

DCM=dichloromethane

DEAD=diethyl azodicarboxylate

DIEA=diisopropylethylamine

DMAP=4-dimethylaminopyridine

DME=dimethoxyethane

DMF=dimethylformamide

DMSO=dimethyl sulfoxide

Et=ethyl

EtOAc=ethyl acetate

EtOH=ethanol

EDC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

FAB MS=fast atom bombardment mass spectroscopy

HOAc=acetic acid

HOBT or HBT=1-hydroxybenzotriazole

HPLC=high performance liquid chromatography

IPA=isopropyl acetate

LAH=lithium aluminum hydride

LDA=lithium diisopropylamide

m-CPBA or MCPBA=meta-chloroperoxybenzoic acid

Me=methyl

MeOH=methanol

MOM=methoxymethyl

MTBE=methyl tert-butyl ether

NBS=N-bromosuccinimide

NCS=N-chlorosuccinimide

NMR=nuclear magnetic resonance

Ph=phenyl

PPTS=pyridinium p-toluenesulfonate

t-Bu=tert-butyl

TBAF=tetrabutylammonium fluoride

TEA=triethylamine

Tf=triflate, SO₂ CF₃

TFA=trifluoroacetic acid

THF=tetrahydrofuran

TLC=thin layer chromatography

TMEDA=N, N, N', N'-tetramethylethylenediamine

TMS=trimethylsilyl

TMS-allyl=allyltrimethylsilane

The compounds of the present invention can be prepared readily accordingto the following Flowsheet diagrams and specific examples, ormodifications thereof, using readily available starting materials,reagents and conventional synthesis procedures. In these reactions, itis also possible to make use of variants which are themselves known tothose of ordinary skill in this art, but are not mentioned in greaterdetail.

The general procedure for making the compounds claimed in this inventioncan be readily understood and appreciated by one skilled in the art fromviewing the following Flowsheet schemes.

Flowsheet 1 illustrates the basic condensation reaction from which allof the claimed compounds can be prepared. As shown, Structure A can bereacted with Structure B in the presence of a suitable solvent andreagent combination to effect the condensation reaction to form theStructure I, which is the generic description of the claimed compoundsin this invention.

The variables Ar, R¹, R², R³ _(n) are as defined in the Summary of theInvention, and claim 1. In light of these examples, other conventionalprocedures will become obvious to one skilled in the art for carryingout the condensation to make the novel compounds of Structure I.##STR7##

Flowsheet 2 describes three different methods for the synthesis of A.First, an aniline 1 can be reacted with a chloroethylbenzylamine 2 ine.g., toluene with heating to yield an aromatic diamine 3, which can besubsequently reacted with a dibromosubstituted ethyl compound 4 in thepresence of iPr₂ NEt in DMF with heating, followed by debenzylation toproduce the starting generic Structure A. Secondly, the aniline 1 can bereacted with the dichloro substituted amine 6 to produce A. Thirdly, thehaloaromatic, where Hal is halogen, can be reacted with the substitutedpiperazine 8 to produce the aromatic substituted piperazine 9 which canthen be deprotected by hydrolysis to yield A. ##STR8##

Flowsheet 3 describes subgeneric Structures A₁ and B₁ and the synthesisof subgeneric Structure II.

As illustrated, the aniline 10, can be condensed with theN-benzyl-N-chloroethylamine 2 in toluene with heating to produce thearomatic diamine 11. The aromatic diamine 11 can then be reacted with R¹substituted dibromoethylene 12 to produce the ring formed piperazine 13,which can be debenzylated with hydrogen gas over palladium catalyst inmethanol to yield the starting intermediate "A₁ ".

The starting intermediate "B₁ " can be made by reacting the acylphenol14 with the hydroxypiperidine 15 in THF with triphenylphosphine and DEADto yield the condensed ether 16. This compound can be converted to thebenzylic acid "B₁ " by treating with thallium nitrate andtrimethoxymethane followed by aqueous methanolic sodium hydroxide. "A₁ "can then be reacted with "B₁ " in the presence of EDC, HOBT, DIEA andDMF to yield subgeneric Structure II. ##STR9##

Flowsheet 4 describes the synthesis of EXAMPLE 1.

As illustrated, a synthesis of the specific Structure A₂ can be carriedout wherein o-toluidine 17, can be condensed with theN-benzyl-N-chloroethylamine 2 in toluene with heating to produce thearomatic diamine 18. The aromatic diamine can be reacted with thecarboxamido dibromoethylene 19 to produce the ring formed piperazine 20,which can be debenzylated with hydrogen gas over palladium catalyst inmethanol to yield the starting intermediate "A₂ "

The synthesis of "B₂ " starts with the diphenol 21, which then can bereacted with the hydroxypiperidine 22 to yield the ether 23. Thephenolic group on ether 23 can be alkylated to produce thetrifluoroethyl derivative 24, which can then undergo the conversion tothe phenylacetic acid compound "B₂ ", with thallium nitrate andtrimethoxymethane in methanol followed by aqueous methanolic sodiumhydroxide. "A₂ " is then reacted with "B₂ " to produce the 25, thetitled compound of Example 1. ##STR10##

Representative compounds of the invention are any or all of thosespecifically set forth in the following Examples. These compounds arenot, however, to be construed as forming the only genus that isconsidered as the invention, and any combination of the compounds ortheir moieties may itself form a genus. The following examples furtherillustrate details for the preparation of the compounds of the presentinvention. Those skilled in the art will readily understand that knownvariations of the conditions and processes of the following preparativeprocedures can be used to prepare these compounds.

In the Examples, dry THF was obtained by distillation from calciumhydride under inert atmosphere. Dry DMF and dry CH₂ Cl₂ were obtained bystoring the reagent grade solvents over 3 Å molecular sieves.Determination of reaction pH was estimated by spotting an aliquot fromthe reaction mixture on wetted E. Merck "colorpHast" pH 1-14 indicatorstrips. Silica coated TLC plates were used to monitor all reactions(Analtech Uniplate, 2.4×10 cm, Silica Gel GF, 250 micron thickness).Pressurized silica gel column chromatography using 230-400 mesh silicagel was performed according to the method of Still, Kahn, and Mitra, J.Org. Chem., 1978, vol. 43, p. 2923. All temperatures are degreesCelsius. ¹ H NMR spectra were measured at 300 MHz on a Varian XL-300, at400 MHz on a Varian XL-400, using (CH₃)₄ Si as an internal standard. AllNMR spectra for the compounds of the Examples which follow wereconsistent with the assigned structures. Fast atom bombardment massspectra were obtained on a VG-ZAB-HF spectrometer.

MeOH(NH₃) used for TLC analysis and for silica gel coulmn chromatographyrefers to a methanol solution saturated with ammonia gas at 0° C.2,2,2-Trifluoroethyl trifluoromethylsulfonate and2,2,3,3,3-pentafluoropropyl trifluoromethylsulfonate were prepared bythe method of R. L. Hansen, J. Orge. Chem., 1965, vol. 30, pp.4322-4.

Analytical HPLC were run on a Spectra Physics SP4270/8800 instrumentusing the following conditions:

Column: Vydac C₁₈, 0.21×15 cm

UV detection at 214 nm

Mobile Phase for Methods A-C:

A=0.1% by volume TFA in H₂ O

B=0.1% by volume TFA in acetonitrile

Mobile Phase for Method D:

A=0.1% by volume H₃ PO₄ in H₂ O

B=0.1% by volume H₃ PO₄ in acetonitrile

Method A:

Gradient T=0 min, 95% A, 5% B

T=15 min, 0% A, 100% B

Flow=2.0 mL/min

Method B:

Gradient T=0 min, 95% A, 5% B

T=15 min, 5% A, 95% B

Flow=1.5 mL/min

Method C:

Gradient T=0 min, 95% A, 5% B

T=45 min, 5% A, 95% B

Flow=1.5 mL/min

Method D:

Gradient T=0 min, 95% A, 5% B

T=15 min, 5% A, 95% B

Flow=1.5 mL/min

EXAMPLE 11-(4-(4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine##STR11##

Steps 1-4. 2-Benzylaminoethanol (20 g, 0.13 mol) was converted toN-(2-chloroethyl)-N-benzylamine hydrochloride with thionyl chloride (31g, 0.26 mol) according to the procedure described in J. Chem. Soc. 1955,p. 896. N-(2-chloroethyl)-N-benzylamine hydrochloride (4.0 g, 19 mmol)was converted to N-benzyl-N'-(2-methylphenyl)-1,2-diaminoethanehydrochloride by the procedure of Syn. Comm., 1988, vol. 18, p. 45-50,using o-toluidine (6.1 g, 57 mmol) in place of aniline.1-Benzyl-2-carbamoyl-4-(2-methylphenyl)-piperazine was prepared from2,3-dibromopropionamide (7.9 g, 34 mmol) by the procedure of J. Med.Chem., 1992, vol. 35, p. 743-750 usingN-benzyl-N'-(2-methylphenyl)-1,2-diaminoethane hydrochloride (4.95 g, 18mmol) in place of N-benzyl-N'-phenyl-1,2-diaminoethane hydrochloride(TLC: Rf=0.51 (5% methanol in methylene chloride; FABMS: M+H @ m/e=310).1-Benzyl-2-carbamoyl-4-(2-methyl-phenyl)piperazine (2.64 g, 8.53 mmol)and palladium hydroxide/carbon (430 mg) were combined in a mixture ofmethanol (35 ml) and ethanol (35 ml) and shaken in an atmosphere ofhydrogen at 55 psi for 6 hours at ambient temperature. The mixture wasfiltered and the filtrate was concentrated in vacuo. The residue wasreconcentrated in vacuo from ether three times to provide2-carbamoyl-4-(2-methylphenyl)piperazine as a solid.

Step 5. To a stirred solution of 2,4-dihydroxyacetophenone (6.0 g, 39.5mmol) and triphenylphosphine (15.5 g, 59.2 mmol) in dry THF (100 mL) at0° C. was added a solution of N-tert-butyloxycarbonyl-4-piperidinol(11.9 g, 59.2 mmol) and DEAD (10.3 g, 59.2 mmol) in dry THF (75 mL)dropwise over a period of 2 h. The mixture was warmed to ambienttemperature over 2 h and stirred for an additional 18 h. The solvent wasremoved under reduced pressure and the residue was suspended in ether.The solid triphenylphosphine oxide was removed by filtration and thefiltrate was concentrated under reduced pressure and purified bypressurized silica gel column chromatography using 4:1 hexane:EtOAc aseluant. Concentration of the product-containing fractions gave4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-hydroxyacetophenone as asolid (HPLC retention time=6.15 min (method A); TLC R_(f) =0.49 (1:3EtOAc:hexanes)).

Step 6. To a stirred solution of4-(N-tert-butyloxy-carbonyl-4-piperidinyloxy)-2-hydroxyacetophenone (4.0g, MW=335, 11.9 mmol) from Step 5 above and 2,2,2-trifluoroethyltrifluoromethyl-sulfonate (5.4 g, 26 mmol) in DMF (50 mL) at 0° C. wasadded Cs₂ CO₃ (8.5 g, 26 mmol). The mixture was stirred at 0° C. for 2 hand then at ambient temperature for 2 h. The solvent was removed underreduced pressure and the residue was partitioned between EtOAc (150 mL)and saturated aqueous NaHCO₃ (200 mL). The organic phase was dried(MgSO₄), filtered, and the solvent was removed under reduced pressure.The residue was purified by pressurized silica gel column chromatographyusing 4:1 hexanes:EtOAc as eluant. The product-containing fractions wereevaporated under reduced pressure to give4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)-acetophenoneas a colorless gum (HPLC retention time=10.6 min (method A); TLC R_(f)32 0.45 (1:3 EtOAc:hexanes)).

Step 7. To a stirred solution of4-(N-tert-butyloxy-carbonyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)acetophenone(4.0 g, 9.88 mmol) from Step 6 above and trimethyl orthoformate (3.15 g,29.7 mmol) in MeOH (100 mL) was added thallium trinitrate trihydrate(4.39 g, 9.88 mmol). The mixture was stirred at ambient temperature for18 h. A white solid precipitate was removed by filtration and thefiltrate solvent was evaporated under reduced pressure. The residue waspartitioned between EtOAc (100 mL) and saturated aqueous NaHCO₃ (200mL). The organic phase was dried (MgSO₄), filtered, and the solvent wasremoved under reduced pressure. HPLC analysis (method A) of the residueindicated a ca. 4:1 mixture of desired product (retention time=10.8 min)and product in which the Boc group had been lost (retention time 6.5min). The residue was dissolved in DMF (20 mL) and di-tert-butyldicarbonate (0.72 g, 3.3 mmol) was added. The mixture was stirred atambient temperature for 2 h. The solvent was removed under reducedpressure and the residue was partitioned between EtOAc (100 mL) andsaturated aqueous NaHCO₃ (50 mL). The organic phase was dried (MgSO₄),filtered, and the solvent was removed under reduced pressure. Theresidue was purified by pressurized silica gel column chromatographyusing 4:1 hexanes:EtOAc as eluant. The product-containing fractions wereevaporated under reduced pressure to give methyl4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetateas a colorless gum (HPLC retention time=10.8 min (method A); TLC R_(f)=0.46 (1:3 EtOAc:hexanes)).

Step 8. To a stirred solution of methyl4-(N-tert-butyloxy-carbonyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetate(3.0 g, MW=435, 6.90 mmol) from Step 7 above in MeOH (25 mL) was added asolution of aqueous NaOH (6.9 mL of a 2.0 N solution, 13.8 mmol). Themixture was refluxed for 3 h and then cooled to ambient temperature. Thesolvents were removed under reduced pressure and the residue waspartitioned between EtOAc (100 mL) and 0.25 M aqueous citric acid (75mL). The organic phase was separated and washed with H₂ O (25 mL) andbrine (25 mL). The organic phase was dried (MgSO₄), filtered, and thesolvent was removed under reduced pressure.4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylaceticacid was obtained as an amorphous solid (HPLC retention time=9.4 min(method A)).

Step 9. To a stirred solution of4-(N-tert-butyloxy-carbonyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylaceticacid (2.0 g, MW=421, 4.75 mmol) from Step 8 above,2-carbamoyl-4-(2-methylphenyl)piperazine (0.89 g, 4.8 mmol) from Step 4above, and HOBT (0.73g, 4.8 mmol) in DMF (75 mL) was added EDC (2.08 g,7.1 mmol) and DIEA (1.2 mL, 7.2 mmol). The mixture was stirred atambient temperature for 14 h. The solvent was removed under reducedpressure and the residue was partitioned between EtOAc (100 mL) and 0.25M aqueous citric acid (75 mL). The organic phase was separated andwashed with H₂ O (25 mL), saturated aqueous NaHCO₃ (75 mL), and brine(25 mL). The organic phase was dried (MgSO₄), filtered, and the solventwas removed under reduced pressure. The residue was purified bypressurized silica gel column chromatography using EtOAc as eluant. Theproduct-containing fractions were evaporated under reduced pressure togive1-(4-(N-Boc-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)-piperazineas an amorphous solid.

Step 10. Into a stirred solution of1-(4-(N-Boc-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine(3.5 g, 5.4 mmol) from Step 9 above in EtOAc (125 mL) at 0° C. wasbubbled HCl gas for 15 min. The resulting suspension was stirred at 0°C. for 45 min. Excess HCl was removed by bubbling argon though themixture for 15 min. Ether (125 mL) was added and the cold suspension wasfiltered. The solids were washed with additional ether and then driedunder reduced pressure for 18 h to give the hydrochloride salt of thetitle compound as an amorphous white powder.

HPLC retention time=7.35 min (method A) TLC R_(f) =0.22 (90:10:0.5 CH₂Cl₂ :MeOH:NH₄ OH); FAB MS: m/z=535 (M⁺ +H); combustion analysis: C₂₇ H₃₃F₃ N₄ O₄, 1.5 HCl, 1.0 H₂ O; Calculated C, 53.40; H, 6.06; N, 9.23;Found C, 53.56; H, 6.15; N, 9.21

EXAMPLE 21-(4-(N-cyclopropylmethyl-4-piperidinyloxy)-2-(2,2,2-trifluoro-ethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenylpiperazine##STR12##

To a solution of1-(4-(4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazinehydrochloride (0.30 g, 0.5 mmol) from Example 1 in MeOH (7.5 mL) wasadded sodium acetate (82 mg, 1.0 mmol), acetic acid (0.10 mL, 1.7 mmol),and cyclopropane carboxaldehyde (75 mg, 1.1 mmol). The mixture wasstirred at ambient temperature for 30 min and NaBH₃ CN (61 mg, 1.0 mmol)was added. The solution was stirred for 18 h and the solvent was removedunder reduced pressure. The residue was dissolved in EtOAc (50 mL) andwashed with saturated aqueous NaHCO₃ (3×25 mL). The organic phase wasdried (MgSO₄), filtered, and the solvent was removed under reducedpressure. The residue was purified by pressurized silica gel columnchromatography using 95:5:0.25 CH₂ Cl₂ :MeOH:NH₄ OH as eluant. The freebase was dissolved in MeOH containing 2.5 equivalents of 3 N aqueousHCl. The resulting solution was evaporated under reduced pressure andthe residue was dissolved in a minimum volume of MeOH and added dropwiseto rapidly stirred ether. The precipitate was collected by filtrationand dried in vacuo to give the hydrochloride salt of the title compoundas an amorphous solid.

HPLC retention time=9.76 min (method B) TLC R_(f) =0.28 (95:5:0.5 CH₂Cl₂ :MeOH:NH₄ OH); FAB MS: m/z=589 (M⁺ +H); combustion analysis: C₃₁ H₃₉F₃ N₄ O₄, 2.15 HCl, 0.15 ether; Calculated C, 55.97; H, 6.34; N, 8.26;Found C, 55.98; H, 6.54; N, 8.36

EXAMPLE 31-(4-(N-methylsulfonyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)-phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine##STR13##

To a solution of1-(4-(4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazinehydrochloride (0.20 g, 0.35 mmol) from Example 1 in CH₂ Cl₂ (20 mL) wasadded methanesulfonoyl chloride (0.045 g, 0.39 mmol) and DIEA (0.14 mL,0.80 mmol). The solution was stirred at ambient temperature for 6 h andthe solvent was removed under reduced pressure. The residue wasdissolved in EtOAc (50 mL) and washed with 0.25 M aqueous citric acid(25 mL), H₂ O (25 mL), and saturated aqueous NaHCO₃ (25 mL). The organicphase was dried (MgSO₄), filtered, and the solvent was removed underreduced pressure. The residue was purified by pressurized silica gelcolumn chromatography using 97:3 CH₂ Cl₂ :MeOH. The product-containingfractions were combined and the solvent was removed under reducedpressure. The residue was dissolved in CH₂ Cl₂ :hexane, and evaporationof this solution under reduced pressure gave the title compound as anamorphous solid.

HPLC retention time=11.2 min (method B) TLC R_(f) =0.25 (95:5 CH₂Cl2:MeOH); FAB MS: m/z=613 (M⁺ +H), 0.25 CH₂ Cl₂, 0.35 hexane;combustion analysis: C₂₈ H₃₅ F₃ N₄ O₆ S, 0.25 CH₂ Cl₂, 0.35 hexane;Calculated C, 64.89; H, 6.13; N, 8.44; Found C, 54.97; H, 6.17; N, 8.43

EXAMPLE 41-(4-(N-acetyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenyl-acetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine##STR14##

To a solution of1-(4-(4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazinehydrochloride (0.30 g, 0.5 mmol) from Example 1 in CH₂ Cl₂ (50 mL) wasadded acetic anhydride (0.11 mL, 1.0 mmol) and DIEA (0.17 mL, 1.0 mmol).The solution was stirred at ambient temperature for 1 h and the solventwas removed under reduced pressure. The residue was dissolved in EtOAc(100 mL) and washed with 0.25 M aqueous citric acid (50 mL), H₂ O (25mL), and saturated aqueous NaHCO₃ (75 mL). The organic phase was dried(MgSO₄), filtered, and the solvent was removed under reduced pressure.The residue was dissolved in CH₂ Cl₂ and 2 equivalents of TFA wereadded. Evaporation of this solution under reduced pressure gave the TFAsalt of title compound as an amorphous solid.

HPLC retention time=9.29 min (method B) TLC R_(f) =0.15 (95:5:0.5 CH₂Cl₂ :MeOH:NH₄ OH); FAB MS: m/z=577 (M⁺ +H), 1.0 TFA, 0.7 CH₂ Cl₂ ;combustion analysis: C₂₉ H₃₅ F₃ N₄ O₅, 1.0 TFA, 0.7 CH₂ Cl₂ ; CalculatedC, 50.76; H, 5.03; N, 7.47; Found C, 50.77; H, 4.79; N, 7.29

EXAMPLE 51-(4-(N-2-methyl-2-hydroxypropyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)-piperazine##STR15##

To a solution of1-(4-(4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazinehydrochloride (0.10 g, 0.17 mmol) from Example 2 in MeOH (10 mL) wasadded DIEA (0.035 mL, 0.20 mmol) and isobutylene oxide (1 mL, 13 mmol).The solution was stirred for 18 h at ambient temperature and the solventwas removed under reduced pressure. The residue was dissolved in EtOAc(50 mL) and washed with saturated aqueous NaHCO₃ (25 mL). The organicphase was dried (MgSO₄), filtered, and the solvent was removed underreduced pressure. The residue was purified by preparative reverse phaseHPLC using a water:acetonitrile gradient containing 0.1% TFA. Theproduct-containing fractions were lyophilized to give the TFA salt ofthe title compound as an amorphous solid.

HPLC retention time=8.40 min (method B) TLC R_(f) =0.26 (92:8:0.8 CH₂Cl₂ :MeOH:NH₄ OH); FAB MS: m/z=607 (M⁺ +H); combustion analysis: C₃₁ H₄₁F₃ N₄ O₅, 1.8 TFA, 0.1 H₂ O ; Calculated C, 51.07; H, 5.33; N, 6.89;Found C, 51.08; H, 5.25; N, 6.83

EXAMPLE 61-(4-amino-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)niperazine##STR16##

Step 1. To a stirred solution of 4-nitro-2-hydroxytoluene (5 g, 33 mmol)in DMF (75 mL) at 0° C. was added 2,2,2-trifluoroethyltrifluoromethylsulfonate (13 g, 62 mmol) and Cs₂ CO₃ (20 g, 62 mmol).The mixture was stirred at 0° C. for 30 min and then at ambienttemperature for 2 h. The mixture was diluted with EtOAc (150 mL) andfiltered. The filtrate solvents were removed under reduced pressure andthe residue was dissolved in EtOAc (200 mL) and washed with saturatedaqueous NaHCO₃ (2×100 mL) and brine (50 mL). The organic phase was dried(MgSO₄), filtered, and the volume was reduced to ˜50 mL under reducedpressure, at which point the product had begun to crystallize. Themixture was cooled to -20° C. for 14 h, filtered, and the solids werewashed with cold EtOAc. 4-Nitro-2-(2,2,2-trifluoroethoxy)toluene wasobtained as a crystalline solid (HPLC retention time=10.0 min (methodA)).

Step 2. 4-Nitro-2-(2,2,2-trifluoroethoxy)toluene (2.0 g, 9.0 mmol) fromStep 1 above was dissolved in MeOH (20 mL) and shaken with palladiumblack (100 mg) under 50 psig of hydrogen on a Parr apparatus for 2 h.The catalyst was removed by filtration and the solvent was removed underreduced pressure to give 4-amino-2-(2,2,2-trifluoroethoxy)toluene as agum.

Step 3. To a stirred solution of4-amino-2-(2,2,2-trifluoroethoxy)toluene (1.2 g, 6.2 mmol) from Step 2above in DMF (20 mL) was added di-tert-butyldicarbonate (3.4 g, 16 mmol)and DMAP (0.76 g, 6.2 mmol). The mixture was stirred at ambienttemperature for 2 h and then at 40° C. for 14 h. The solvent was removedunder reduced pressure and the residue was partitioned between EtOAc(100 mL) and 0.25 M aqueous citric acid (75 mL). The organic phase wasseparated, washed with water (50 mL), saturated aqueous NaHCO₃ (50 mL),dried (MgSO₄), filtered, and the solvent was removed under reducedpressure. The residue was purified by pressurized silica gel columnchromatography using a gradient elution of 5-15% EtOAc:hexanes to give4-(N,N-di-(tert-butylcarbonyl)amino)-2-(2,2,2-trifluoroethoxy)-tolueneas a colorless gum (TLC R_(f) =0.55 (15% EtOAc:hexanes)).

Step 4. To a stirred solution of4-(N,N-di-(tert-butyl-carbonyl)-amino)-2-(2,2,2-trifluoroethoxy)toluene(2.0 g, 5.0 mmol) from Step 3 above in CCl₄ (75 mL) was added NBS (0.90g, 5.0 mmol) and AIBN (0.2 g, 1.2 mmol). The mixture was refluxed for 2h. The solvent was removed under reduced pressure and the residue waspartitioned between EtOAc (100 mL) and saturated aqueous NaHCO₃ (2×50mL). The organic phase was dried (MgSO₄), filtered, and the solvent wasremoved under reduced pressure. The residue was purified by pressurizedsilica gel column chromatography using a gradient elution of 5-15%EtOAc:hexanes to give4-(N,N-di-(tert-butylcarbonyl)amino)-2-(2,2,2-trifluoroethoxy)benzylbromide as a colorless gum (TLC R_(f) =0.50 (15% EtOAc:hexanes)).

Step 5. To a stirred solution of4-(N,N-di-(tert-butyl-carbonyl)-amino)-2-(2,2,2-trifluoroethoxy)benzylbromide (1.5 g, 3.2 mmol) from Step 4 above in DMF (20 mL) was addedNaCN (0.23 g, 4.8 mmol). The mixture was stirred at ambient temperaturefor 24 h. The solvent was removed under reduced pressure and the residuewas purified by pressurized silica gel column chromatography using 15%EtOAc:hexanes as eluant to give an inseparable mixture (˜3:1) of4-(N,N-di-(tert-butylcarbonyl)amino)-2-(2,2,2-trifluoroethoxy)phenyl-acetonitrileand4-(tert-butylcarbonylamino)-2-(2,2,2-trifluoroethoxy)-phenylacetonitrile(TLC R_(f) =0.28 (15% EtOAc:hexanes)).

Step 6. A ˜3:1 mixture of4-(N,N-di-(tert-butylcarbonyl)-amino)-2-(2,2,2-trifluoroethoxy)phenylacetonitrileand4-(tert-butylcarbonylamino)-2-(2,2,2-trifluoroethoxy)phenylacetonitrile(1.1 g) from Step 5 above was refluxed in a 1:1 mixture of acetic acidand concentrated aqueous HCl for 3 h. The solvents were removed underreduced pressure. The residue was dissolved in water and the solvent wasevaporated under reduced pressure to remove residual acetic acid.4-Amino-2-(2,2,2-trifluoroethoxy)phenylacetic acid hydrochloride wasobtained as a colorless gum (HPLC retention time=4.2 min (method A)).

Step 7. Into a stirred solution of4-amino-2-(2,2,2-trifluoroethoxy)phenylacetic acid hydrochloride (0.95g, 3.5 mmol) from Step 6 above in MeOH (25 mL) at 0° C. was bubbled HClgas for 10 min. The resulting solution was warmed to ambient temperatureand stirred for 14 h. The solvent was removed under reduced pressure togive methyl 4-amino-2-(2,2,2-trifluoroethoxy)phenylacetate hydrochlorideas a solid (HPLC retention time=5.6 min (method A)).

Step 8. To a solution of methyl4-amino-2-(2,2,2-trifluoroethoxy)phenylacetate hydrochloride (1.0 g, 3.5mmol) from Step 7 above in DMF (20 mL) was addeddi-tert-butyl-dicarbonate (0.85 g, 3.9 mmol) and DIEA (1.2 mL, 7.0mmol). The solution was stirread at ambient temperature for 14 h. Thesolvent was removed under reduced pressure and the residue waspartitioned between EtOAc (100 mL) and 0.25 M aqueous citric acid (50mL). The organic phase was separated, washed with water (25 mL),saturated aqueous NaHCO₃ (50 mL), dried (MgSO₄), filtered, and thesolvent was removed under reduced pressure. The residue was purified bypressurized silica gel column chromatography using 20% EtOAc:hexanes aseluant. Methyl4-(tert-butyloxycarbonylamino)-2-(2,2,2-trifluoroethoxy)phenylacetatewas obtained as a colorless gum (TLC R_(f) =0.40 (20% EtOAc:hexanes);HPLC retention time=10.3 min (method A)).

Step 9. To a stirred solution of methyl4-(tert-butyloxycarbonyl-amino)-2-(2,2,2-trifluoroethoxy)phenylacetate(0.90 g, 2.5 mmol) in MeOH (15 mL) was added aqueous NaOH (2.5 mL of a 3N solution, 7.5 mmol). The mixture was refluxed for 1 h. The solventswere removed under reduced pressure and the residue was partitionedbetween EtOAc (100 mL) and 0.25 M aqueous citric acid (25 mL). Theorganic phase was separated, washed with water (25 mL), dried (MgSO₄),filtered, and the solvent was removed under reduced pressure to give4-(tert-butyloxycarbonylamino)-2-(2,2,2-trifluoroethoxy)-phenylaceticacid as an amorphous solid (HPLC retention time=8.8 min (method A)).

Step 10. To a stirred solution of4-(tert-butyloxycarbonylmino)-2-(2,2,2-trifluoroethoxy)phenylacetic acid(0.20 g, 0.59 mmol) from Step 9 above in DMF (10 mL) was added2-carbamoyl-4-(2-methylhenyl)piperazine (0.13 g, 0.59 mmol) from Step 4of Example 1, HOBT (0.09 g, 0.6 mmol), EDC (0.15 g, 0.90 mmol), and DIEA(0.15 mL, 0.90 mmol). The solution was stirred at ambient temperaturefor 14 h during which time a precipitate had formed. The mixture wascooled, filtered, and the solid was washed with EtOAc and dried underreduced pressure to give1-(2-(2,2,2-trifluoroethoxy)-4-(tert-butyloxycarbonylamino)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)-piperazineas an amorphous solid (HPLC retention time=10.0 min (method A); TLCR_(f) =0.40 (3:1 EtOAc:hexanes).

Step 11. Into a stirred solution of1-(2-(2,2,2-trifluoroethoxy)-4-(tert-butyloxycarbonylamino)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine(0.22 g, 0.41 mmol) from Step 10 above in EtOAc (75 mL) at 0° C. wasbubbled HCl gas for 15 min. The resulting suspension was stirred at 0°C. for 45 min. Excess HCl was removed by bubbling argon though themixture for 15 min. Ether (75 mL) was added and the cold suspension wasfiltered. The solids were washed with EtOAc and dried under reducedpressure for 18 h to give the hydrochloride salt of the title compoundas an amorphous white powder.

HPLC retention time=7.2 min (method A) TLC R_(f) =0.50 (90:10:0.5 CH₂Cl₂ :MeOH:NH₄ OH); FAB MS: m/z=451 (M⁺ +H); combustion analysis: C₂₂ H₂₅F₃ N₄ O₃, 2.0 HCl, 1.0 H_(20;) 0.7 EtOAc; Calculated C, 49.07; H, 5.57;N, 9.87; Found C, 49.02; H, 5.49; N, 9.88

EXAMPLE 71-(4-(5-benzimidazolylcarbonylamino)-2-(2,2,2-trifluoroethoxy)-phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine##STR17##

To a stirred solution of1-(4-amino-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine(0.20 g, 0.44 mmol) from Example 6 in DMF (10 mL) was addedbenzimidazole 5-carboxylic acid (0.077 g, 0.48 mmol), HOBT (0.09 g, 0.6mmol), EDC (0.15 g, 0.90 mmol), and DIEA (0.083 mL, 0.5 mmol). Thesolution was stirred at ambient temperature for 14 h during which time aprecipitate had formed. The mixture was cooled, filtered, and the solidwas washed with EtOAc. The solid was dissolved in CH₃ CN:H₂ O containingTFA and purified by preparative reverse phase HPLC. Theproduct-containing fractions were lyophilized to give the TFA salt ofthe title compound as an amorphous solid.

HPLC retention time=8.3 min (method A) TLC R_(f) =0.22 (90:10:0.5 CH₂Cl₂ :MeOH:NH₄ OH); FAB MS: m/z=595 (M⁺ +H); combustion analysis: C₃₀ H₂₉F₃ N₆ O₄, 2.1 TFA, 2.25 H₂ O; Calculated C, 46.97; H, 4.10; N, 9.61;Found C, 46.90; H, 3.97; N, 9.61

EXAMPLE 81-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)-piperazine##STR18##

Step 1. To a stirred solution of methyl 2-hydroxyphenylacetate (10 g, 60mmol) in DMF (150 mL) at 0° C. was added 2,2,2-trifluoroethyltrifluoromethansulfonate (94 mmol) and Cs₂ CO₃ (38 g, 120 mmol). Themixture was stirred at 0° C. for 2 h and then at ambient temperature for12 h. The solids were removed by filtration and the filtrate solventswere removed under reduced pressure. The residue was partitioned betweenEtOAc (250 mL) and water (2×100 mL). The organic phase was dried(MgSO₄), filtered, and the solvent was removed under reduced pressure.The residue was purified by silica gel chromatography to give methyl2-(2,2,2-trifluoroethoxyphenylacetate as a colorless liquid (HPLCretention time=9.3 min (method E); TLC R_(f) =0.6 (2:1 hexanes:EtOAc)).

Step 2. To a stirred solution of methyl2-(2,2,2-trifluoroethoxyphenylacetate (2 g, 8 mmol) from Step 1 above inDME (20 mL) was added aqueous LiOH (20 mL of a 1.0 M solution, 20 mmol).The solution was stirred at ambient temperature for 1 h. The solutionwas concentrated under reduced pressure to ˜10 mL and 0.25 M aqueouscitric acid (20 mL) was added. The precipitate was removed by filtrationand dried under reduced pressure to give2-(2,2,2-trifluoroethoxyphenylacetic acid as a crystalline solid (HPLCretention time=7.4 min (method E)).

Step 3. To a stirred solution of 2-(2,2,2-trifluoroethoxyphenylaceticacid (0.10 g, 0.45 mmol) from Step 2 above and2-carbamoyl-4-(2-methylphenyl)piperazine (0.10 g, 0.46 mmol) from Step 4of Example 1 in DMF (15 mL) was added HOBT (0.075 g, 0.5 mmol), EDC(0.22 g, 0.75 mmol), and DIEA (0.13 mL, 0.75 mmol). The solution wasstirred at ambient temperature for 14 h and the solvent was removedunder reduced pressure. The residue was partitioned between EtOAc (100mL) and 0.25 M aqueous citric acid (25 mL). The organic phase wasseparated and washed with H₂ O (25 mL), saturated aqueous NaHCO₃ (25mL), and brine (25 mL). The organic phase was dried (MgSO₄), filtered,and the solvent was removed under reduced pressure. The residue waspurified by pressurized silica gel coulmn chromatography using 5:95MeOH:CH₂ Cl₂ as eluant. The title compound was obtained as an amorphoussolid.

HPLC retention time=8.8 min (method A) TLC R_(f) =0.2 (5:95 MeOH:CH₂Cl₂); FAB MS: m/z=436 (M⁺ +H); combustion analysis: C₂₂ H₂₄ F₃ N₃ O₃,0.15 CH₂ Cl₂ ; Calculated C, 59.35; H, 5.47; N, 9.38; Found C, 59.41; H,5.53; N, 9.54

EXAMPLE 91-(2-trifluoromethylphenylacetyl)-2-carbamoyl-4-(2-methylphenyl)-₋₋##STR19##

The title compound was prepared from 2-trifluoromethylphenylacetic acidand 2-carbamoyl-4-(2-methylphenyl)piperazine using the procedure givenin Step 3 of Example 8. The title compound was obtained as an amorphoussolid.

HPLC retention time=8.82 min (method A) TLC R_(f) =0.4 (95:5 CH₂ Cl₂:MeOH); FAB MS: m/z=406 (M⁺ +H); combustion analysis: C₂₁ H₂₂ F₃ N₃ O₂,0.05 CH₂ Cl₂, 0.05 MeOH; Calculated C, 61.62; H, 5.47; N, 10.22; FoundC, 61.57; H, 5.41; N, 10.42

EXAMPLE 101-(2-trifluoromethoxyphenylacetyl)-2-carbamoyl-4-(2-methylphenyl)-piperazine##STR20##

Step 1. To a stirred solution of 2-trifluoromethoxybenzoic acid (1.0 g,5.2 mmol) in THF (25 mL) at 0° C. was added borane-THF complex (15 mL ofa 1.0 M solution in THF, 15 mmol). The solution was warmed to ambienttemperature and stirred for 14 h. The solvent was removed under reducedpressure and the residue was partitioned between EtOAc (75 mL) andsaturated aqueous NaHCO₃ (75 mL). The organic phase was dried (MgSO₄),filtered and the solvent was removed under reduced pressure to give2-trifluoromethoxybenzyl alcohol as a colorless liquid (TLC R_(f) =0.2(1:3 EtOAc-hexanes)).

Step 2. To a stirred solution of 2-trifluoromethoxybenzyl alcohol (0.81g, 4.5 mmol) from Step 1 above in ether (20 mL) at 0° C. was addedtriphenylphosphine (2.4 g, 9.2 mmol) and CBr₄ (3.0 g, 9.2 mmol). Themixture was warmed to ambient temperature and stirred for 18 h. Theether was decanted from the gummy precipitate of triphenylphosphineoxide and evaporated under reduced pressure. The residue was purified bypressurized silica gel column chromatography using hexanes as eluant togive 2-trifluoromethoxybenzyl bromide as a colorless liquid (TLC R_(f)=0.80 (hexanes)).

Step 3. To a stirred solution of 2-trifluoromethoxybenzyl bromide (0.95g, 3.9 mmol) from Step 2 above in DMF (5 mL) was added NaCN (0.21 g, 4.3mmol). The mixture was stirred at ambient temperature for 14 h and thesolvent was removed under reduced pressure. The residue was purified bypressurized silica gel column chromatography using 15% EtOAc-hexanes aseluant to give 2-trifluoromethoxyphenylacetonitrile as a colorlessliquid (TLC R_(f) =0.6 (solvent)).

Step 4. 2-Trifluoromethoxyphenylacetonitrile (0.49 g, 2.6 mmol) fromStep 3 above was refluxed for 3 h in a 1:1 mixture of acetic acid andconcentrated aqueous HCl. The solvents were removed under reducedpressure. The residue was partitioned between EtOAc (75 mL) and water(2×25 mL). The organic phase was separated, dried (MgSO₄), filtered, andevaporated under reduced pressure to give 2-trifluoromethoxyphenylaceticacid as an amorphous solid (HPLC retention time=6.8 min (method A)).

Step 5. To a stirred solution of 2-trifluoromethoxyphenylacetic acid(0.10 g, 0.48 mmol) from Step 4 above and2-carbamoyl-4-(2-methylphenyl)piperazine (0.10 g, 0.46 mmol) from Step 4of Example 1 in DMF (10 mL) was added HOBT (0.075 g, 0.5 mmol), EDC(0.22 g, 0.75 mmol), and DIEA (0.13 mL, 0.75 mmol). The solution wasstirred at ambient temperature for 14 h and the solvent was removedunder reduced pressure. The residue was partitioned between EtOAc (50mL) and 0.25 M aqueous citric acid (25 mL). The organic phase wasseparated and washed with H₂ O (25 mL), saturated aqueous NaHCO₃ (25mL), and brine (25 mL). The organic phase was dried (MgSO₄), filtered,and the solvent was removed under reduced pressure. The residue waspurified by pressurized silica gel column chromatography using EtOAc aseluant. The product-containing fractions were evaporated under reducedpressure and the residue was lyophilized from CH₃ CN:H₂ O to give thetitle compound as an amorphous solid.

HPLC retention time=9.1 min (method A) TLC R_(f) =0.2 (5:95 MeOH:CH₂Cl₂); FAB MS: m/z=422 (M⁺ +H); combustion analysis: C₂₁ H₂₂ F₃ N₃ O₃,0.3 H₂ O, 0.1 CH₃ CN; Calculated C, 59.08; H, 5.36; N, 10.08; Found C,59.10; H, 5.30; N, 10.17

EXAMPLE 111-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-4-(2-cyanophenyl)piperazine##STR21##

The title compound was prepared using the procedure given in Example 12using 2-cyanophenylpiperazine in place of 2-methoxyphenylpiperazine. Theproduct was purified by pressurized silica gel column chromatographyusing 1:1 EtOAc:hexanes as eluant to give the title compound as anamorphous solid.

HPLC retention time=9.7 min (method A) TLC R_(f) =0.5 (1:1EtOAc:hexanes); FAB MS: m/z=404 (M⁺ +H); combustion analysis: C₂₁ H₂₀ F₃N₃ O₂, 0.3 H₂ O; Calculated C, 61.69; H, 5.08; N, 10.28; Found C, 61.74;H, 4.92; N, 9.98

EXAMPLE 121-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-4-(2-methoxyphenyl)-piperazine##STR22##

To a stirred solution of 2-methoxyphenylpiperazine (0.062 g, 0.32 mmol)and 2-(2,2,2-trifluoroethoxy)phenylacetic acid (0.075 mg, 0.32 mmol) inDMF (1 mL) was added EDC (0.115 g, 0.40 mmol), HOBT (0.049 g, 0.32mmol), and DIEA (0.055 mL, 0.32 mmol). The mixture was stirred atambient temperature for 18 h. The DMF was removed under reducedpressure. The residue was partitioned between EtOAc and saturatedaqueous NaHCO₃. The EtOAc layer was dried (MgSO₄), filtered, and thesolvent was removed under reduced pressure. The residue was purified bypreparative TLC using 1:1 EtOAc:hexane as eluant. The title compound wasobtained as an amorphous solid.

HPLC retention time=8.9 min (method D) TLC R_(f) =0.45 (1:1EtOAc:hexane); FAB MS: m/z=409 (M⁺ +H); combustion analysis: C₂₁ H₂₃ F₃N₂ O₃ ; Calculated C, 61.76; H, 5.68; N, 6.86; Found C, 61.65; H, 5.86;N, 6.60

EXAMPLE 131-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-4-(2-chlorophenyl)piperazine##STR23##

The title compound was prepared and purified using the procedure givenin Example 12 using 2-chlorophenylpiperazine in place of2-methoxyphenylpiperazine.

HPLC retention time=11.5 min (method D) TLC R_(f) =0.57 (1:1EtOAc:hexanesa); FAB MS: m/z=380 (M⁺ +H); combustion analysis: C₁₉ H₂₀F₃ N₃ O₂ ; Calculated C, 58.19; H, 4.88; N, 6.78; Found C, 57.72; H,5.03; N, 6.38

EXAMPLE 141-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-4-(2-pyridyl)piperazine##STR24##

The title compound was prepared and purified using the procedure givenin Example 12 using 2-pyridylpiperazine in place of2-methoxyphenylpiperazine.

HPLC retention time=5.3 min (method D) TLC R_(f) =0.39 (1:1EtOAc:hexanes); FAB MS: m/z=380 (M⁺ +H); combustion analysis: C₁₉ H₂₀ F₃N₃ O₂ ; Calculated C, 60.15; H, 5.31; N, 11.08; Found C, 60.25; H, 5.47;N, 10.70

EXAMPLE 151-(4-acetylamino-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine##STR25##

To a solution of1-(4-amino-2-(2,2,2-trifluoroethoxy)-phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine(0.10 g, 0.18 mmol) from Example 6 in CH₂ Cl₂ (10 mL) at 0° C. was addedacetyl chloride (0.014 mL, 0.2 mmol) and DIEA (0.04 mL, 0.22 mmol). Thesolution was stirred at ambient temperature for 2 h and the solvent wasremoved under reduced pressure. The residue was dissolved in EtOAc (100mL) and washed with 0.25 M aqueous citric acid (50 mL), H₂ O (25 mL),and saturated aqueous NaHCO₃ (75 mL). The organic phase was dried(MgSO₄), filtered, and the solvent was removed under reduced pressure.The residue was purified by preparative reverse phase HPLC using awater:acetonitrile gradient containing 0.1% TFA. The product-containingfractions were lyophilized to give the TFA salt of title compound as anamorphous solid.

HPLC retention time=8.28 min (method A) TLC R_(f) =0.3 (95:5 CH₂ Cl₂:MeOH); FAB MS: m/z=493 (M⁺ +H); combustion analysis: C₂₄ H₂₇ F₃ N₄ O₄,0.45 TFA, 0.9 H₂ O ; Calculated C, 53.40; H, 5.26; N, 10.00; Found C,53.41; H, 5.25; N, 9.79

EXAMPLE 161-(4-chloro-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine##STR26##

4-Chloro-2-(2,2,2-trifluoroethoxy)phenylacetic acid was prepared from4-chloro-2-hydroxytoluene using procedures analogous to those given inSteps 1-4 of Example 21 and then coupled to2-carbamoyl-4-(2-methylphenyl)piperazine using a procedure analogous tothat given in Step 5 of Example 21. The product was purified bypreparative reverse phase HPLC using a water:acetinitrile gradientcontaining 0.1% TFA. The product-containing fractions were lyophilizedto give the TFA salt of the title compound as an amorphous solid.

HPLC retention time=23.5 min (method C) TLC R_(f) =0.5 (95:5:0.5 CH₂ Cl₂:MeOH:NH₄ OH); FAB MS: m/z=470 (M⁺ +H); combustion analysis: C₂₂ H₂₃ClF₃ N₃ O₃, 0.8 TFA; Calculated C, 50.51; H, 4.28; N, 7.49; Found C,50.57; H, 4.28; N, 7.39

EXAMPLE 171-(5-chloro-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine##STR27##

5-Chloro-2-(2,2,2-trifluoroethoxy)phenylacetic acid was prepared from5-chloro-2-hydroxytoluene using procedures analogous to those given inSteps 1-4 of Example 21 and then coupled to2-carbamoyl-4-(2-methylphenyl)piperazine using a procedure analogous tothat given in Step 5 of Example 21. The product was purified bypreparative reverse phase HPLC using a water:acetinitrile gradientcontaining 0.1% TFA. The product-containing fractions were lyophilizedto give the TFA salt of the title compound as an amorphous solid.

HPLC retention time=23.3 min (method C) TLC R_(f) =0.6 (95:5:0.5 CH₂ Cl₂:MeOH:NH₄ OH); FAB MS: m/z=470 (M⁺ +H); combustion analysis: C₂₂ H₂₃ClF₃ N₃ O₃, 0.75 TFA, 0.05 H₂ O; Calculated C, 50.73; H, 4.32; N, 7.55;Found C, 50.72; H, 4.24; N, 7.44

EXAMPLE 181-(4-trifluoromethyl-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine##STR28##

4-Trifluoromethyl-2-(2,2,2-trifluoroethoxy)phenylacetic acid wasprepared from 2-fluoro-5-trifluoromethylacetophenone using proceduresanalogous to those given in Steps 1-3 of Example 19 and then coupled to2-carbamoyl-4-(2-methylphenyl)piperazine using a procedure analogous tothat given in Step 4 of Example 19. The product was purified bypressurized silica gel column chromatography using 95:5 CH₂ Cl₂ :MeOH aseluant. The title compound was obtained as an amorphous solid.

HPLC retention time=10.1 min (method A) TLC R_(f) =0.5 (95:5 CH₂ Cl₂:MeOH); FAB MS: m/z=504 (M⁺ +H); combustion analysis: C₂₃ H₂₃ F₆ N₃ O₃,1.4 CH₂ Cl₂ ; Calculated C, 47.09; H, 4.18; N, 6.75; Found C, 47.20; H,3.74; N, 7.19

EXAMPLE 191-(5-trifluoromethyl-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine##STR29##

Step 1. To a stirred solution of 2,2,2-trifluoroethanol (0.53 mL, 7.3mmol) in THF (20 mL) at 0° C. was added potassium tert-butoxide (7.3 mLof a 1.0 M solution in THF, 7.3 mmol). The mixture was stirred at 0° C.for 10 min and 2-fluoro-5-trifluoromethyl-acetophenone (1.0 g, 4.9 mmol;HPLC retention time=8.7 min (method A)) was added. The mixture wasstirred at 0° C. for 15 min and then at ambient temperature for 5 h. Thesolvent was removed under reduced pressure and the residue waspartitioned between EtOAc (100 mL) and saturated aqueous NaHCO₃ (2×50mL). The organic phase was dried (MgSO₄), filtered, and the solvent wasremoved under reduced pressure to give2-(2,2,2-trifluoroethoxy)-5-trifluoromethylacetophenone as a gum (HPLCretention time=10.0 min (method A)).

Step 2. To a stirred solution of2-(2,2,2-trifluoroethoxy)-5-trifluoromethylacetophenone (0.97 g, 3.4mmol) from Step 1 above in MeOH (17 mL) was added trimethyl orthoformate(1.1 mL, 1.1 mmol) and thallium trinitrate trihydrate (1.5 g, 3.4 mmol).The mixture was stirred at ambient temperature for 48 h. The precipitatewhich had formed was removed by filtration and the filtrate solvent wasremoved under reduced pressure. The residue was partitioned betweenEtOAc (100 mL) and saturated aqueous NaHCO₃ (2×50 mL). The organic phasewas dried (MgSO₄), filtered, and the solvent was removed under reducedpressure to give methyl2-(2,2,2-trifluoroethoxy)-5-trifluoromethylphenylacetate as a gum (HPLCretention time=10.0 min (method A)).

Step 3. To a stirred solution of methyl2-(2,2,2-trifluoroethoxy)-5-trifluoromethylphenylacetate (1.07 g, 3.5mmol) from Step 2 above in THF (8 mL) and water (2 mL) was added LiOH(0.20 g, 4.8 mmol). The mixture was stirred at ambient temperature for24 h. The reaction was acidified to pH 2 with 5 N aqueous HCl and thesolvents were removed under reduced pressure. The residue was purifiedby pressurized silica gel column chromatography using a gradient elutionof 0-50% MeOH:CH₂ Cl₂ to give2-(2,2,2-trifluoroethoxy)-5-trifluoromethylphenylacetic acid as a gum(HPLC retention time=8.7 min (method A)).

Step 4. To a stirred solution of2-(2,2,2-trifluoroethoxy)-5-trifluoromethylphenylacetic acid (0.10 g,0.33 mmol) from Step 3 above, 1-2-carbamoyl-4-(2-methylphenyl)piperazine(0.08 g, 0.36 mmol) from Step 4 of Example 1, and HOBT (0.06 g, 0.4mmol) in DMF (5 mL) was added EDC (0.10 g, 0.5 mmol) and DIEA (0.088 mL,0.5 mmol). The mixture was stirred at ambient temperature for 14 h. Thesolvent was removed under reduced pressure and the residue was purifiedby pressurized silica gel column chromatography using 5:95 MeOH:CH₂ Cl₂as eluant. The product-containing fractions were evaporated underreduced pressure to give the title compound as an amorphous powder.

HPLC retention time=9.96 min (method A) TLC R_(f) =0.3 (5:95 MeOH:CH₂Cl₂); FAB MS: m/z=504 (M⁺ +H), 0.45 CH₂ Cl₂, 0.05 H₂ O; combustionanalysis: C₂₃ H₂₃ F₆ N₃ O₃, 0.45 CH₂ Cl₂, 0.05 H₂ O; Calculated C,51.91; H, 4.46; N, 7.75; Found C, 51.94; H, 4.33; N, 7.67

EXAMPLE 201-(4-(2-pyridinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine##STR30##

Step 1. To a stirred solution of 2-hydroxy-4-fluoroacetophenone (10 g,65 mmol) in DMF (300 mL) at 0° C. was added 2,2,2-trifluoroethyltrifluoromethanesulfonate (25 g, 120 mmol) and Cs₂ CO₃ (39 g, 120 mmol).The mixture was stirred at 0° C. for 2 h and then at ambient temperaturefor 14 h. EtOAc (300 mL) was added and the solid was removed byfiltration. The filtrate solvents were removed under reduced pressureand the residue was partitioned between EtOAc (250 mL) and saturatedaqueous NaHCO₃ (2×100 mL). The organic phase was dried (MgSO₄),filtered, and the solvent was removed under reduced pressure. Theresidue was purified by pressurized silica gel column chromatographyusing 5% EtOAc:hexanes as eluant to give2-(2,2,2-trifluoroethoxy)-4-fluoroacetophenone as a colorless oil (HPLCretention time=8.8 min (method A); TLC R_(f) =0.55 (20% EtOAc:hexanes)).

Step 2. To a stirred solution of2-(2,2,2-trifluoroethoxy)-4-fluoroacetophenone (0.40 g, 1.7 mmol) fromStep 1 above in DMF (10 mL) was added 2-hydroxypyridine (0.24 g, 2.5mmol) and Cs₂ CO₃ (1.1 g, 3.4 mmol). The mixture was heated to 50° C.and stirred for 14 h. The solids were removed by filtration and thefiltrate solvent was removed under reduced pressure. The residue waspartitioned between EtOAc and water. The organic phase was dried(MgSO₄), filtered, and the solvent was removed under reduced pressure togive 2-(2,2,2-trifluoroethoxy)-4-(2-pyridyloxy)acetophenone as anamorphous solid (HPLC retention time=6.6 min (method A)).

Step 3. To a stirred solution of2-(2,2,2-trifluoroethoxy)-4-(2-pyridyloxy)acetophenone (0.48 g, 1.5mmol)) from Step 2 above in MeOH (8 mL) was added trimethyl orthoformate(0.50 mL, 4.5 mmol) and thallium trinitrate trihydrate (0.68 g, 1.5mmol). The mixture was stirred at ambient temperature for 14 h. Theprecipitate that had formed was removed by filtration and the filtratesolvent was removed under reduced pressure. The residue was partitionedbetween EtOAc (75 mL) and saturated aqueous NaHCO₃ (2×50 mL). Theorganic phase was dried (MgSO₄), filtered, and the solvent was removedunder reduced pressure to give methyl2-(2,2,2-trifluoroethoxy)-4-(2-pyridyloxy)phenylacetate as an oil (HPLCretention time=6.6 min (method A)).

Step 4. To a stirred solution of methyl2-(2,2,2-trifluoroethoxy)-4-(2-pyridyloxy)phenylacetate (0.45 g, 1.3mmol) from Step 3 above in THF (4 mL) and water (1 mL) was added LiOH·H₂O (0.065 g, 1.5 mmol). The mixture was stirred at ambient temperaturefor 14 h. The solution was adjusted to pH 3 by the addition of 5 Naqueous HCl and the solvents were removed under reduced pressure. Theresidue was purified by pressurized silica gel column chromatographyusing a gradient elution of 0-20% MeOH:CH₂ Cl₂ to give2-(2,2,2-trifluoroethoxy)-4-(2-pyridyloxy)-phenylacetic acid as a gum(HPLC retention time=5.4 min (method A)).

Step 5. To a stirred solution of2-(2,2,2-trifluoroethoxy)-4-(2-pyridyloxy)phenylacetic acid (0.10 g,0.31 mmol) from Step 4 above and2-carbamoyl-4-(2-methylphenyl)piperazine (0.08 g, 0.35 mmol) from Step 4of Example 1 in DMF (2 mL) was added HOBT (0.06 g, 0.35 mmol), EDC (0.10g, 0.5 mmol), and DIEA (0.09 mL, 0.5 mmol). The solution was stirred atambient temperature for 14 h and the solvent was removed under reducedpressure. The residue was partitioned between EtOAc (50 mL) andsaturated aqueous NaHCO₃ (2×25 mL). The organic phase was dried (MgSO₄),filtered, and the solvent was removed under reduced pressure. Theresidue was purified by pressurized silica gel column chromatographyusing 95:5 CH₂ Cl₂ :MeOH as eluant. The product-containing fractionswere evaporated under reduced pressure to give the title compound as anamorphous solid.

HPLC retention time=7.96 min (method A) TLC R_(f) =0.25 (95:5 CH₂ Cl₂:MeOH); FAB MS: m/z=529 (M⁺ +H); combustion analysis: C₂₇ H₂₇ F₃ N₄ O₄,1.15 CH₂ Cl₂ ; Calculated C, 53.99; H, 4.72; N, 8.95; Found C, 54.06; H,4.52; N, 8.68

EXAMPLE 211-(3-chloro-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine##STR31##

Step 1. To a solution of 2-hydroxy-3-chlorotoluene (5 g, 35 mmol) in DMF(75 mL) at 0° C. was added 2,2,2-trifluoroethoxytrifluoromethylsulfonate (16 g, 70 mmol) and Cs₂ CO₃ (22 g, 68 mmol).The mixture was stirred at 0° C. for 3 h and then at ambient temperaturefor 14 h. The solvent was removed under reduced pressure. The residuewas partitioned between EtOAc (150 mL) and water (3×75 mL). The organicphase was dried (MgSO₄), filtered, and the solvent was removed underreduced pressure. The residue was purified by pressurized silica gelcolumn chromatography using 1:4 EtOAc:hexanes as eluant to give2-(2,2,2-trifluoroethoxy)-3-chlorotoluene as an oil.

Step 2. To a stirred solution of2-(2,2,2-trifluoroethoxy)-3-chlorotoluene (2.4 g, 11 mmol) from Step 1above in CCl₄ (40 mL) was added NBS (2.1 g, 11 mmol) and AIBN (1.8 g, 11mmol). The mixture was refluxed for 8 h. The solvent was removed underreduced pressure and the residue was partitioned between EtOAc andsaturated aqueous NaHCO₃. The organic phase was dried (MgSO₄), filtered,and the solvent was removed under reduced pressure. The residue waspurified by silica gel column chromatography using hexanes as eluant.2-(2,2,2-trifluoroethoxy)-3-chlorobenzyl bromide was obtained as an oil(HPLC retention time=22.3 min (method D)).

Step 3. To a solution of 2-(2,2,2-trifluoroethoxy)-3-chlorobenzylbromide (1.6 g, 5.4 mmol) from Step 2 above in DMF (12 mL) was addedNaCN (0.28 g, 5.7 mmol). The solution was stirred at ambient temperaturefor 14 h. The solvent was removed under reduced pressure and the residuewas partitioned between EtOAc and saturated aqueous NaHCO₃. The organicphase was dried (MgSO₄), filtered, and the solvent was removed underreduced pressure. The residue was purified by pressurized silica gelcolumn chromatography using a gradient elution of 5-20% EtOAc:hexanes togive 2-(2,2,2-trifluoroethoxy)-3-chlorophenylacetonitrile as a colorlessoil.

Step 4. 2-(2,2,2-trifluoroethoxy)-3-chlorophenyl-acetonitrile (1.2 g,5.1 mmol) from Step 3 above was refluxed in a 2:1 mixture of acetic acidand concentrated aqueous HCl (25 mL) for 12 h. The solvents were removedunder reduced pressure and the residue was partitioned between EtOAc andwater. The organic phase was washed with water, dried (MgSO₄), filtered,and the solvent was removed under reduced pressure to give2-(2,2,2-trifluoroethoxy)-3-chlorophenylacetic acid as an oil.

Step 5. To a stirred solution of2-(2,2,2-trifluoroethoxy)-3-chlorophenylacetic acid (0.14 g, 0.53 mmol)from Step 4 above, 2-carbamoyl-4-(2-methylphenyl)piperazine (0.12 g,0.53 mmol) from Step 4 of Example 1, and HOBT (0.08 g, 0.53 mmol) in DMF(5 mL) was added EDC (0.15 g, 0.8 mmol) and DIEA (0.14 mL, 0.8 mmol).The mixture was stirred at ambient temperature for 14 h. The solvent wasremoved under reduced pressure and the residue was purified bypreparative reverse phase HPLC using a H₂ O:CH₃ CN gradient containing0.1% TFA. The product-containing fractions were lyophilized to give thetitle compound as an amorphous powder.

HPLC retention time=24.6 min (method C) TLC R_(f) =0.5 (95:5:0.5 CH₂ Cl₂:MeOH:NH₄ OH); FAB MS: m/z=470 (M⁺ +H); combustion analysis: C₂₂ H₂₃ClF₃ N₃ O₃, 0.75 TFA; Calculated C, 50.82; H, 4.31; N, 7.57; Found C,50.80; H, 4.21; N, 7.61

EXAMPLE 221-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-4-(3-trifluoromethylphenyl)-piperazine##STR32##

The title compound was prepared and purified using the procedure givenin Example 12 using 3-trifluoromethylphenyl-piperazine in place of2-methoxyphenylpiperazine.

HPLC retention time=11.6 min (method D) TLC R_(f) =0.62 (1:2EtOAc:hexanes); FAB MS: m/z=xx (M⁺ +H; combustion analysis: C₂₁ H₂₀ F₆N₂ O₂), 0.1 ether; Calculated C, 56.64; H, 4.66; N, 6.17; Found C,56.95; H, 4.75; N, 5.95

EXAMPLE 231-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-4-(2-pyrazinyl)piperazine##STR33##

The title compound was prepared and purified using the procedure givenin Example 12 using 2-pyrazinylpiperazine in place of2-methoxyphenylpiperazine.

HPLC retention time=7.5 min (method D) TLC R_(f) =0.34 (1:1EtOAc:hexanes); FAB MS: m/z=381 (M⁺ +H); combustion analysis: C₁₈ H19F₃N₄ O₂ ; Calculated C, 56.91; H, 5.12; N, 14.59; Found C, 57.27; H, 5.06;N, 14.91

EXAMPLE 241-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-4-(2-pyrimidinyl)piperazine##STR34##

The title compound was prepared and purified using the procedure givenin Example 12 using 2-pyrimidinylpiperazine in place of2-methoxyphenylpiperazine.

HPLC retention time=8.2 min (method D) TLC R_(f) =0.42 (1:1EtOAc:hexanes); FAB MS: m/z=381 (M⁺ +H); combustion analysis: C₁₈ H19F₃N₄ O₂ ; Calculated C, 56.84; H, 5.03; N, 14.73; Found C, 57.07; H, 5.06;N, 14.53

EXAMPLE 251-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-4-(2,6-dimethylphenyl)-piperazine##STR35##

The title compound was prepared and purified using the procedure givenin Example 12 using 2,6-dimethylphenylpiperazine in place of2-methoxyphenylpiperazine.

HPLC retention time=12 min (method D) TLC R_(f) =0.27 (1:2EtOAc:hexanes); FAB MS: m/z=407 (M⁺ +H); combustion analysis: C₂₂ H₂₅ F₃N₂ O₂ ; Calculated C, 65.01; H, 6.20; N, 6.89; Found C, 64.69; H, 6.20;N, 6.69

EXAMPLE 261-(4-(1-triazolyl)-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine##STR36##

Step 1. To a stirred solution of2-(2,2,2-trifluoroethoxy)-4-fluoroacetophenone (0.40 g, 1.7 mmol) fromStep 1 of Example 20 in DMF (10 mL) was added 1,2,4-triazole (0.18 g,2.5 mmol) and Cs₂ CO₃ (1.1 g, 3.4 mmol). The mixture was heated to 50°C. and stirred for 24 h. The solids were removed by filtration and thefiltrate solvent was removed under reduced pressure. The residue waspartitioned between EtOAc and water. The organic phase was dried(MgSO₄), filtered, and the solvent was removed under reduced pressure.The residue was purified by pressurized silica gel column chromatographyusing a gradient elution of 10-40% EtOAc:hexanes to give2-(2,2,2-trifluoroethoxy)-4-(1-triazolyl)acetophenone as an amorphoussolid (HPLC retention time=7.6 min (method A)).

Step 2. To a stirred solution of2-(2,2,2-trifluoroethoxy)-4-(1-triazolyl)acetophenone (0.45 g, 1.6mmol)) from Step 1 above in MeOH (8 mL) was added trimethyl orthoformate(0.52 mL, 4.8 mmol) and thallium trinitrate trihydrate (0.71 g, 1.6mmol). The mixture was stirred at ambient temperature for 14 h. Theprecipitate that had formed was removed by filtration and the filtratesolvent was removed under reduced pressure. The residue was partitionedbetween EtOAc (75 mL) and saturated aqueous NaHCO₃ (2×50 mL). Theorganic phase was dried (MgSO₄), filtered, and the solvent was removedunder reduced pressure to give methyl2-(2,2,2-trifluoroethoxy)-4(1-triazolyl)phenylacetate as an oil (HPLCretention time=7.6 min (method A)).

Step 3. To a stirred solution of methyl2-(2,2,2-trifluoroethoxy)-4-(1-triazolyl)phenylacetate (0.54 g, 1.7mmol) from Step 2 above in THF (10 mL) and water (2.5 mL) was addedLiOH·H₂ O (0.11 g, 2.6 mmol). The mixture was stirred at ambienttemperature for 14 h. The solution was adjusted to pH 2 by the additionof 5 N aqueous HCl and the solvents were removed under reduced pressureto give 2-(2,2,2-trifluoroethoxy)-4-(1-triazolyl)phenylacetic acid wasobtained as a gum (HPLC retention time=6.0 min (method A)).

Step 4. To a stirred solution of2-(2,2,2-trifluoroethoxy)-4-(1-triazolyl)phenylacetic acid (0.10 g, 0.33mmol) from Step 3 above and 2-carbamoyl-4-(2-methylphenyl)piperazine(0.08 g, 0.35 mmol) from Step 4 of Example 1 in DMF (2 mL) was addedHOBT (0.06 g, 0.35 mmol), EDC (0.10 g, 0.5 mmol), and DIEA (0.09 mL, 0.5mmol). The solution was stirred at ambient temperature for 14 h and thesolvent was removed under reduced pressure. The residue was partitionedbetween EtOAc (50 mL) and 0.25 M aqueous citric acid (25 mL). Theorganic phase was separated and washed with H₂ O (10 mL), and saturatedaqueous NaHCO₃ (25 mL). The organic phase was dried (MgSO₄), filtered,and the solvent was removed under reduced pressure. The residue waspurified by preparative reverse phase HPLC using a water:acetonitrilemobil phase containing 0.1% TFA. The TFA salt of the title compound wasobtained an amorphous solid by lyophilization of the product-containingfractions.

HPLC retention time=8.17 min (method A) TLC R_(f) =0.2 (95:5 CH₂ Cl₂:MeOH); FAB MS: m/z=503 (M⁺ +H), 2.0 TFA; combustion analysis: C₂₄ H₂₅F₃ N₆ O₃, 2.0 TFA; Calculated C, 46.03; H, 3.72; N, 11.50; Found C,46.00; H, 3.51; N, 11.55

EXAMPLE 271-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-4-(4-fluorophenyl)piperazine##STR37##

The title compound was prepared and purified using the procedure givenin Example 12 using 4-fluorophenylpiperazine in place of2-methoxyphenylpiperazine.

HPLC retention time=10.3 min (method D) TLC R_(f) =0.59 (1:2EtOAc:hexanes); FAB MS: m/z=397 (M⁺ +H); combustion analysis: C₂₀ H₂₀ F₄N₂ O₂ ; Calculated C, 60.60; H, 5.09; N, 7.07; Found C, 60.50; H, 5.16;N, 7.16

EXAMPLE 281-(4-fluoro-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine:##STR38##

Step 1. To a stirred solution of NaOH (2.0 g, 50 mmol) in water (15 mL)at 0° C. was added bromine (3.0 g, 19 mmol). The solution was stirredfor 10 min and a solution of2-(2,2,2-trifluoroethoxy)-4-fluoroacetophenone (1.5 g, 6.4 mmol)) fromStep 1 of Example 20 in dioxane (25 mL) was added dropwise over 15 min.The mixture was stirred at 0° C. for 15 min, at ambient temperature for12 h ,and then at reflux for 1.5 h. The mixture was cooled to 0° C. andacidified to pH 2 by the addition of 6 N aqueous HCl. The mixture wasconcentrated under reduced pressure and then extracted with CH₂ Cl₂(2×75 mL). The combined organic extracts were dried (MgSO₄), filtered,and the solvent was removed under reduced pressure to give2-(2,2,2-trifluoroethoxy)-4-fluorobenzoic acid as an amorphous solid(HPLC retention time=7.1 min (method A)).

Step 2. To a stirred solution of2-(2,2,2-trifluoroethoxy)-4-fluorobenzoic acid (2.0 g, 8.4 mmol) fromStep 1 above in THF (25 mL) at 0° C. was added BH₃.THF complex (25 mL ofa 1.0 M solution in THF, 25 mmol). The mixture was stirred at 0° C. for30 min and then at ambient temperature for 6 h. Aqueous NaOH (20 mL of a4 N solution, 80 mmol) was added and the solvents were removed underreduced pressure. The residue was partitioned between EtOAc (100 mL) andwater (2×50 mL). The organic phase was dried (MgSO₄), filtered, and thesolvent was removed under reduced pressure to give2-(2,2,2-trifluoroethoxy)-4-fluorobenzyl alcohol as an oil (HPLCretention time=7.3 min (method A)).

Step 3. To a stirred solution of2-(2,2,2-trifluoroethoxy)-4-fluorobenzyl alcohol (1.2 g, 5.3 mmol) fromStep 2 above in ether (30 mL) was added CBr₄ (3.0 g, 9.2 mmol) andtriphenylphosphine (2.4 g, 9.2 mmol). The mixture was stirred at ambienttemperature for 14 h. Triphenylphosphine oxide was removed by filtrationand the filtrate was diluted with EtOAc (50 mL) and washed withsaturated aqueous NaHCO₃ (2×50 mL). The organic phase was dried (MgSO₄),filtered, and the solvent was removed under reduced pressure. Theresidue was purified by pressureized silica gel column chromatographyusing a gradient elution of 0-5% EtOAc:hexanes to give2-(2,2,2-trifluoroethoxy)-4-fluorobenzyl bromide as a colorless oil(HPLC retention time=10.4 min (method A)).

Step 4. To a stirred solution of2-(2,2,2-trifluoroethoxy)-4-fluorobenzyl bromide (0.80 g, 2.7 mmol) fromStep 3 above in DMF (14 mL) was added NaCN (0.20 g, 4.0 mmol). Themixture was stirred at ambient temperature for 14 h. The solvent wasremoved under reduced pressure and the residue was partitioned betweenEtOAc (100 mL) and saturated aqueous NaHCO₃ (2×50 mL). The organic phasewas dried (MgSO₄), filtered, and the solvent was removed under reducedpressure to give 2-(2,2,2-trifluoroethoxy)-4-fluorophenyl-acetonitrileas an oil (HPLC retention time=8.7 min (method A)).

Step 5. To a stirred solution of2-(2,2,2-trifluoroethoxy)-4-fluorophenylacetonitrile (0.60 g, 2.7 mmol)from Step 4 above in acetic acid (10 mL) was added 12 N aqueous HCl (5mL). The mixture was refluxed for 4 h. The solvents were removed underreduced pressure and the residue was partitioned between EtOAc (100 mL)and water (2-50 mL). The organic phase was dried (MgSO₄), filtered, andthe solvent was removed under reduced pressure to give2-(2,2,2-trifluoroethoxy)-4-fluorophenylacetic acid as an amorphoussolid (HPLC retention time=7.5 min (method A)).

Step 6. To a stirred solution of2-(2,2,2-trifluoroethoxy)-4-fluorophenylacetic acid (0.15 g, 0.60 mmol)from Step 5 above and 2-carbamoyl-4-(2-methylphenyl)piperazine (0.13 g,0.66 mmol) from Step 4 of Example 1 in DMF (3 mL) was added HOBT (0.11g, 0.78 mmol), EDC (0.17 g, 0.9 mmol), and DIEA (0.16 mL, 0.9 mmol). Thesolution was stirred at ambient temperature for 14 h and the solvent wasremoved under reduced pressure. The residue was partitioned betweenEtOAc (50 mL) and 0.25 M aqueous citric acid (25 mL). The organic phasewas separated and washed with H₂ O (10 mL) and saturated aqueous NaHCO₃(25 mL). The organic phase was dried (MgSO₄), filtered, and the solventwas removed under reduced pressure. The residue was purified bypressurized silica gel column chromatography using 5:95 MeOH:CH₂ Cl₂ aseluant. Evaporation of the product-containing fractions gave the titlecompound as an amorphous solid. HPLC retention time=9.16 min (method A)TLC R_(f) =0.25 (5:95 MeOH:CH₂ Cl₂); FAB MS: m/z=454 (M⁺ +H), 0.4 CH₂Cl₂ ; combustion analysis: C₂₂ H₂₃ F₄ N₃ O₃, 0.4 CH₂ Cl₂ ; Calculated C,57.43; H, 5.12; N, 8.97; Found C, 57.44; H, 4.89; N, 9.22

EXAMPLE 291-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-4-(2-naphthyl)piperazine##STR39##

The title compound was prepared and purified using the procedure givenin Example 12 using 2-naphthylpiperazine in place of2-methoxyphenylpiperazine.

HPLC retention time=12.1 min (method D) TLC R_(f) =0.63 (1:2EtOAc:hexanes); FAB MS: m/z=429 (M⁺ +H); combustion analysis: C₂₄ H₂₃ F₃N₂ O₂ ; Calculated C, 67.28; H, 5.41; N, 6.54; Found C, 67.33; H, 5.55;N, 6.38

EXAMPLE 301-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-N-methylcarbamoyl-4-(2-methylphenyl)piperazine##STR40##

Step 1. To a solution of1-benzyl-2-carbamoyl-4-(2-methylphenyl)piperazine (1.5 g, 4.8 mmol) fromStep 3 of Example 1 in acetonitrile (125 mL) was addeddi-tert-butyldicarbonate (3.2 g, 14.6 mmol), and DMAP (0.29 g, 2.4mmol). The mixture was stirred at ambient temperature for 24 h. Thesolvent was removed under reduced pressure and the residue was purifiedby pressurized silica gel column chromatography using 95:5 hexanes:EtOAcas eluant to give1-benzyl-2-N,N-di(tert-butyloxycarbonyl)carbamoyl-4-(2-methylphenyl)piperazineas a dense gum (TLC Rf=0.59 (85:15 hexanes:EtOAc)).

Step 2. Into a solution of1-benzyl-2-N,N-di(tert-butyloxycarbonyl)carbamoyl-4-(2-methylphenyl)piperazinefrom the previous step (0.20 g, 0.39 mmol) in EtOH (5 mL) at 0° C. wasbubbled methylamine gas for 10 min. The mixture was stirred at 0° C. for2 h, and the solvent was evaporated under reduced pressure. The residuewas purified by pressureized silica gel column chromatography using 4:1hexanes:EtOAc as eluant to give1-benzyl-2-N-methylcarbamoyl-4-(2-methylphenyl)piperazine as anamorphous solid (TLC Rf=0.10 (85:15 hexanes:EtOAc)).

Step 3. To a solution of1-benzyl-2-N-methylcarbamoyl-4-(2-methylphenyl)piperazine from theprevious step (0.11 g, 0.34 mmol) in EtOH (3 mL) was added 10% palladiumon carbon (20 mg). The mixture was stirred at ambient temperature und 1atmophere of hydrogen gas for 3 h. The hydrogen was purged with argonand the catalyst was removed by filtration through celite. The solventwas removed under reduced pressure to give2-N-methylcarbamoyl-4-(2-methylphenyl)piperazine as an oil (TLC Rf=0.46(96:4:0.4 CH₂ Cl₂ :MeOH:NH₄ OH)).

Step 4. 2-N-methylcarbamoyl-4-(2-methylphenyl)-piperazine from theprevious step and 2-(2,2,2-trifluoroethoxy)-phenylacetic acid from Step2 of Example 8 were coupled using the procedure given in Example 12. Thecrude product was purified by pressurized silica gel columnchromatography using 3:2 EtOAc:hexanes as eluant. The title compound wasobtained as an amorphous solid.

HPLC retention time=9.2 min (method A) TLC R_(f) =0.3 (3:2EtOAc:hexanes); FAB MS: m/z=450 (M⁺ +H), 0.15 EtOAc, 0.35 H₂ O ;combustion analysis: C₂₃ H₂₆ F₃ N₃ O₃, 0.15 EtOAc, 0.35 H₂ O ;Calculated C, 60.43; H, 6.00; N, 8.96; Found C, 60.43; H, 5.93; N, 8.95

EXAMPLE 311-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-N-ethylcarbamoyl-4-(2-methylphenyl)piperazine##STR41##

The title compound was prepared using the methods given in Example 30,except that ethylamine was used in place of methylamine in Step 2. Thecrude product was purified by pressurized silica gel columnchromatography using 3:2 EtOAc:hexanes as eluant to give the titlecompound as an amorphous solid.

HPLC retention time=9.7 min (method A) TLC R_(f) =0.14 (7:3hexanes:EtOAc); FAB MS: m/z=464 (M⁺ +H); combustion analysis: C₂₄ H₂₈ F₃N₃ O₃, 0.1 H₂ O; Calculated C, 61.94; H, 6.11; N, 9.03; Found C, 61.95;H, 6.11; N, 9.00

EXAMPLE 321-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-N,N-dimethylcarbamoyl-4-(2-methylphenyl)piperazine##STR42##

Step 1. To a solution of1-benzyl-2-carbamoyl-4-(2-methylphenyl)piperazine (0.10 g, 0.32 mmol)from Step 3 of Example 1 in DMF (1 mL) at 0° C. was added NaH (0.025 gof a 60% dispersion in mineral oil, 1.0 mmol). The mixture was stirredat 0° C. for 1 h and then iodomethane (0.061 mL, 1.0 mmol) was added andthe mixture was stirred at ambient temperature for 4 h. More NaH wasadded (0.012 g, 0.50 mmol) and the mixture was warmed to 50° C. for 30min. The mixture was cooled to ambient temperature and additionaliodomethane (0.020 mL, 0.33 mmol) was added. The mixture was stirred atambient temperature for 18 h. Saturated aqueous NaHCO₃ (1 mL) was addedand the solvents were removed under reduced pressure. The reisude waspurified by pressurized silica gel column chromatography using 3:1hexanes:EtOAc as eluant to give1-benzyl-2-N,N-dimethylcarbamoyl-4-(2-methylphenyl)piperazine as acolorless oil (TLC R_(f) =0.20 (3:1 hexanes:EtOAc)).

Steps 2-3. The benzyl group in1-benzyl-2-N,N-dimethylcarbamoyl-4-(2-methylphenyl)piperazine from theprevious step was removed using the procedure given in Step 3 of Example30, and the product,2-N,N-dimethylcarbamoyl-4-(2-methylphenyl)-piperazine, was coupled to2-(2,2,2-trifluoroethoxy)phenylacetic acid from Step 2 of Example 8using the procedure given in Example 12. The crude product was purifiedby pressurized silica gel column chromatography using 3:2 EtOAc:hexanesas eluant. The free base was converted to the hydrochloride salt and thesalt was lyophilized from acetonitrile:water to give the HCl salt of thetitle compound as an amorphous solid.

HPLC retention time=8.67 min (method A) TLC R_(f) =0.31 (3:2EtOAc:hexanes); FAB MS: m/z=464 (M⁺ +H); combustion analysis: C₂₄ H₂₈ F₃N₃ O₃, 0.45 HCl, 0.55 H₂ O; Calculated C, 58.85; H, 6.08; N, 8.58; FoundC, 58.85; H, 6.09; N, 8.32

EXAMPLE 331-(4-(4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine##STR43##

Step 1. To a stirred solution of4-bromo-2-(trifluoro-methoxy)iodobenzene (9.93 g, 28 mmol) in THF (150mL) at -78° C. was added tert-butyllithium (37 mL of a 1.5 M solution inpentane, 56 mmol) dropwise over a period of 20 min. The pale yellowsolution was stirred at -78° C. for 1.5 h when N-formylmorpholine (6.5mL; 58 mmol) was added. The resulting solution was stirred at -78° C.for 15 min and the cooling bath was removed. The mixture was stirred foran additional 1 h, when 0.25 M aqueous citric acid (100 mL) was added.The mixture was diluted with EtOAc (150 mL), the layers were separated,the organic phase was washed with brine (100 mL), dried (MgSO₄),filtered, and the solvent was removed under reduced pressure. Theresidue was purified using pressurized silica gel column chromatographyeluting with hexane to give 4-bromo-2-(trifluoro-methoxy)benzaldehyde asa colorless liquid (TLC R_(f) =0.45 (hexanes)).

Step 2. To a stirred solution of4-bromo-2-(trifluoro-methoxy)benzaldehyde (5.0 g, 19 mmol) from Step 1above in EtOH (100 mL) at 0° C. was added NaBH₄ (0.88 g, 23 mmol). Themixture was stirred for 1 h at 0° C., the cooling bath was removed, andthe solution was stirred at ambient temperature for 14 h. The solventwas removed under reduced pressure and the residue was partitionedbetween EtOAc (150 mL) and saturated aqueous NaHCO₃ (75 mL). The organicphase was separated, dried (MgSO₄), filtered, and the solvent wasremoved under reduced pressure. The residue was purified by pressurizedsilica gel column chromatography using a gradient elution of 5-10%EtOAc:hexanes. 4-Bromo-2-(trifluoromethoxy)benzyl alcohol was obtainedas an amorphous solid by evaporation from CH₂ Cl₂ (TLC R_(f) =0.25 (10%EtOAc:hexanes); HPLC retention time=8.8 min (method A)).

Step 3. To a stirred solution of bromo-2-(trifluoro-methoxy)benzylalcohol (4.8 g, 18 mmol) in CH₂ Cl₂ (100 mL) was addedtert-butylchlorodimethylsilane (4.1 g, 27 mmol), triethylamine (3.8 mL,27 mmol), and DMAP (1.2 g, 9.8 mmol). The mixture was stirred at ambienttemperature for 24 h. The solvent was removed under reduced pressure andthe residue was partitioned between EtOAc (150 mL) and 0.25 M aqueouscitric acid (75 mL). The organic phase was washed with H₂ O (50 mL),saturated aqueous NaHCO₃ (75 mL), dried (MgSO₄), filtered, and thesolvent was removed under reduced pressure. The residue was purified bypressurized silica gel column chromatography using hexanes as eluant togive4-bromo-1-(tert-butyldimethylsilyloxymethyl)-2-trifluoromethoxy-benzeneas a colorless oil (TLC R_(f) =0.60 (hexanes)).

Step 4. To a stirred solution of4-bromo-1-(tert-butyldimethylsilyloxymethyl)-2-trifluoromethoxybenzene(5.5 g, 15 mmol) from Step 3 above in THF (100 mL) at -78° C. was addedn-butyllithium (6.6 mL of a 2.5 M solution in hexanes, 16.5 mmol)dropwise over a period of 10 min. The resulting pale yellow solution wasstirred at -78° C. for 30 min and trimethylborate (1.75 g, 17 mmol) wasadded. The resulting solution was stirred at -78° C. for 5 min and thenwarmed to ambient temperature for 45 min. To the mixture was addedacetic acid (0.90 mL, 15 mmol) and hydrogen peroxide (0.1.7 mL of a 30%solution in water, 17 mmol) and stirring was continued for 1 h. Thesolvent was removed under reduced pressure and the residue waspartitioned between EtOAc (150 mL) and water (2×50 mL). The organiclayer was dried (MgSO₄), filtered, and the solvent was removed underreduced pressure. The residue was purified by pressurized silica gelcolumn chromatography using 10% EtOAc:hexanes as eluant to give4-hydroxy-1-(tert-butyldimethyl-silyloxymethyl)-2-trifluoromethoxybenzeneas a colorless oil (TLC R_(f) =0.40 (10% EtOAc:hexanes)).

Step 5. To a stirred solution of4-hydroxy-1-(tert-butyldimethylsilyloxymethyl)-2-trifluoromethoxybenzene(3.2 g, 10 mmol) from Step 4 above and triphenylphosphine (3.9 g, 15mmol) in THF (50 mL) at 0° C. was added a solution ofN-tert-butyloxycarbonyl-4-piperidinol (3.0 g, 15 mmol) and DEAD (2.6 g,15 mmol) in THF (25 mL) dropwise over a period of 1 h. The mixture wasstirred at 0° C. for 3h and then at ambient temperature for 12 h. Thesolvent was removed under reduced pressure and the residue was suspendedin ether. The solid triphenylphosphine oxide was removed by filtrationand the filtrate was purified by pressurized silica gel columnchromatography using a gradient elution of 5-10% EtOAc:hexanes as eluantto give4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-1-(tert-butyldimethylsilyloxy-methyl)-2-trifluoromethoxybenzeneas a colorless gum.

Step 6. To a stirred solution of4-(N-tert-butyloxy-carbonyl-4-piperidinyloxy)-1-(tert-butyldimethylsilyloxymethyl)-2-trifluoromethoxybenzene(3.5 g, 7.1 mmol) from Step 5 above in THF (50 mL) was added TBAF (8 mLof a 1.0 M solution in THF, 8 mmol). The mixture was stirred at ambienttemperature for 5 minutes and the solvent was removed under reducedpressure. The residue was partitioned between EtOAc (100 mL) and water(2×50 mL). The organic phase was dried (MgSO₄), filtered, and thesolvent was removed under reduced pressure. The residue was purified bypressurized silica gel column chromatography using a gradient elution of25-50% EtOac:hexanes to give4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(trifluoromethoxy)benzylalcohol as a colorless gum (TLC R_(f) =0.24 (25% EtOAc EtOAc:hexanes)).

Step 7. To a stirred solution of4-(N-tert-butyloxy-carbonyl-4-piperidinyloxy)-2-(trifluoromethoxy)benzylalcohol (2.5 g, 6.6 mmol)) from Step 6 above and triphenylphosphine(3.46 g, 13.2 mmol) in ether (100 mL) was added carbon tetrabromide(4.35 g, 13 mmol). The mixture was stirred at ambient temperature for 14h and the ethereal solution was decanted away from the gummy precipitateof triphenylphosphine oxide which had formed. The solvent was removedunder reduced pressure and the residue was purified by pressurizedsilica gel column chromatography using a gradient elution of 10-15%EtOAc:hexanes to give4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(trifluoromethoxy)benzylbromide as a colorless oil (TLC R_(f) =0.55 (25% EtOAc:hexanes)).

Step 8. To a stirred solution of4-(N-tert-butyloxy-carbonyl-4-piperidinyloxy)-2-(trifluoromethoxy)benzylbromide (2.2 g, 5.0 mmol) in DMF (50 mL) was added NaCN (2.7 g, 5.5mmol). The mixture was stirred at ambient temperature for 36 h. Thesolvent was removed under reduced pressure and the residue was purifiedby pressurized silica gel column chromatography using 25% EtOAc:hexanesas eluant to give4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetonitrileas a colorless oil (TLC R_(f) =0.43 (25% EtOAc:hexanes); HPLC retentiontime=11.3 min (method A)).

Step 9.4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetonitrile(1.9 g, 4.3 mmol) from Step 8 above dissolved in a 2:1 mixture of aceticacid and concentrated aqueous HCl (25 mL). Loss of the Boc groupoccurred within the first 5 minutes to give an intermediate which had anHPLC retention time of 6.3 min (method A). The solution was thenrefluxed for 2 h, during which time the 6.3 min peak disappeared and anew peak at 5.9 min appeared. The solvents were removed under reducedpressure. The residue was dissolved in degassed DMF (100 mL) and thesolvent was removed under reduced pressure to minimize the amount ofresidual acetic acid and water in the sample. The crude product,4-(4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetic acid, wasdissolved in DMF (50 mL) and di-tert-butyldicarbonate (1.0 g, 4.6 mmol)and DIEA (2.3 mL, 13 mmol) were added. The solution was stirred atambient temperature for 30 min. The solvent was removed under reducedpressure and the residue was partitioned between EtOAc (100 mL) and 0.25M aqueous citric acid (50 mL). The organic phase was separated, washedwith water (2×25 mL), dried (MgSO₄), filtered, and the solvent wasremoved under reduced pressure to give4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(trifluoromethoxy)phenylaceticacid as a gum (HPLC retention time=10.2 min (method A)).

Step 10. To a stirred solution of4-(N-tert-butyloxy-carbonyl-4-piperidinyloxy)-2-(trifluoromethoxy)phenylaceticacid (0.50 g, 1.15 mmol) from Step 9 above and2-carbamoyl-4-(2-methyl-phenyl)piperazine (0.28 g, 1.1 mmol) from Step 4of Example 1 in DMF (20 mL) was added HOBT (0.175 g, 1.15 mmol), EDC(0.53 g, 1.8 mmol), and DIEA (0.26 mL, 1.5 mmol). The solution wasstirred at ambient temperature for 14 h and the solvent was removedunder reduced pressure. The residue was partitioned between EtOAc (100mL) and 0.25 M aqueous citric acid (75 mL). The organic phase wasseparated and washed with H₂ O (25 mL), saturated aqueous NaHCO₃ (75mL), and brine (25 mL). The organic phase was dried (MgSO₄), filtered,and the solvent was removed under reduced pressure. The residue waspurified by pressurized silica gel column chromatography using EtOAc aseluant. The product-containing fractions were evaporated under reducedpressure to give1-(1-(2-trifluoromethoxy-4-(N-tert-butyoxycarbonyl-4-piperidinyloxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazineas an amorphous solid (HPLC retention time=11 min (method A); TLC R_(f)=0.5 (7:3 EtOAc:hexanes).

Step 11. Into a stirred solution of1-(1-(2-trifluoro-methoxy-4-(N-tert-butyoxycarbonyl-4-piperidinyloxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine(0.65 g, 1.0 mmol) from Step 10 above in EtOAc (75 mL) at 0° C. wasbubbled HCl gas for 15 min. The resulting suspension was stirred at 0°C. for 45 min. Excess HCl was removed by bubbling argon though themixture for 15 min. Ether (75 mL) was added and the cold suspension wasfiltered. The solids were washed with additional ether and dried underreduced pressure for 18 h to give the hydrochloride salt of the titlecompound as an amorphous white powder.

HPLC retention time=7.48 min (method A) TLC R_(f) =0.42 (90:10:0.5 CH₂Cl₂ :MeOH:NH₄ OH); FAB MS: m/z=521 (M⁺ +H), 2.0 HCl, 0.62 H₂ O;combustion analysis: C₂₆ H₃₁ F₃ N₄ O₄, 2.0 HCl, 0.62 H₂ O; Calculated C,51.65; H, 5.71; N, 9.27; Found C, 51.64; H, 5.62; N, 9.21

EXAMPLE 341-(4-(N-acetyl-4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine##STR44##

To a solution of1-(4-(4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazinehydrochloride (0.30 g, 0.5 mmol) from Example 33 in CH₂ Cl₂ (50 mL) wasadded acetic anhydride (0.10 mL, 1.0 mmol) and DIEA (0.17 mL, 1.0 mmol).The solution was stirred at ambient temperature for 1 h and the solventwas removed under reduced pressure. The residue was dissolved in EtOAc(100 mL) and washed with 0.25 M aqueous citric acid (50 mL), H₂ O (25mL), and saturated aqueous NaHCO₃ (75 mL). The organic phase was dried(MgSO₄), filtered, and the solvent was removed under reduced pressure togive the title compound as an amorphous solid.

HPLC retention time=8.8 min (method A) TLC R_(f) =0.40 (95:5 CH₂ Cl₂:MeOH); FAB MS: m/z=566(M⁺ +H); combustion analysis: C₂₈ H₃₃ F₃ N₄ O;Calculated C, 59.46; H, 5.88; N, 9.91; Found C, 59.47; H, 5.46; N, 9.95

EXAMPLE 351-(2-(2,2,2-trifluoroethoxy)phenylacetyl)-4-(3-ethylphenyl)piperazine##STR45##

Step 1. Into a 15 mL round-bottomed flask fitted with a refluxcondensor, a magnetic stirring bar, and a nitrogen inlet was added 1 mLdry toluene followed by 0.016 g (0.09 mmol) PdCl₂ and 0.055 g (0.18mmol) tri-o-tolylphosphine. After stirring for 15 min, an additional 15mL dry toluene was added followed by 0.33 g (1.8 mmol)3-ethylbromobenzene, 0.41 g (2.2 mmol) 1-Boc-piperazine and 0.242 g (2.5mmol) sodium t-butoxide. The reaction was heated to reflux for 18 hr,after which time TLC (20% EtOAc/Hexane) showed the formation of a newspot. The reaction was cooled, diluted with 50 mL of ether, filteredthrough a Celite pad, and extracted with 3×10 mL water and 1×15 mLbrine. The organic phase was dried (Na2SO₄), filtered and the solventremoved in vacuo to get the crude product, which was purified by passingthrough a 2" silica pad (1% to 4% EtOAc/Hexane) to yield1-Boc-4-(3-ethylphenyl)piperazine.

Step 2. 0.037 g (0.128 mmol) 1-Boc-4-(3-ethylphenyl)-piperazine from theprevious step was dissolved in 10 mL EtOAc and cooled to 0° C. using anice bath. HCl gas was then bubbled through the reaction for 10 min,followed by an additional 10 min of stirring. The reaction was warmed toambient temperature and the solvent removed in vacuo. The residue wastaken up in 10 mL CHCl₃ that had been previously saturated with NH₃ gas,the solid NH₄ Cl filtered, and the solvent removed to give1-(3-ethylphenyl)piperazine as the free base.

Step 3. 1-(3-ethylphenyl)piperazine from the previous step was dissolvedin 1 mL dry DMF, and to the solution was added 0.03 g (0.128 mmol)2-(2,2,2-trifluoroethoxy)phenylacetic acid, 0.017 g (0.128 mmol) HOBT,and 0.024 g (0.128 mmol) EDC. The reaction was stirred for 2 days, afterwhich time the solvent was removed in vacuo and the resulting residuepartitioned between EtOAc/H₂ O. The aqueous phase was extracted withEtOAc and the combined organic phases were washed with H₂ O, brine,dried over Na2SO₄ and filtered. Removal of the solvent and subsequentpurification via preparative TLC (2:1 Hexane/EtOAc) yielded the titlecompound as the free base. This was dissolved in 20 mL EtOAc and anexcess of ethanolic HCl was added. The solvent was removed to give theHcl salt of the title compound.

HPLC retention time=11.2 min (method D) TLC R_(f) =0.37 (1:1EtOAc:hexanes); FAB MS: m/z=407 (M⁺ +H); combustion analysis: C₂₂ H₂₅ F₃N₂ O₂, 1.0 HCl, 0.25 ether; Calculated C, 59.86; H, 6.23; N, 6.07; FoundC, 60.25; H, 5.95; N, 6.11

EXAMPLE 36

As a specific embodiment of an oral composition, 100 mg of the compoundof Example 1 is formulated with sufficient finely divided lactose toprovide a total amount of 580 to 590 mg to fill a size O hard gelcapsule.

Also as an embodiment of the instant invention is a use of the compoundsdisclosed herein for preparing a medicament for the purpose oftreating/preventing the clinical conditions for which an oxytocinreceptor antagonist is indicated.

EXAMPLE 37 Rat & Human ot/avp Binding Assays

The high affinity binding of [³ H]oxytocin (OT) to uterine tissue and [³H]arginine vasopressin (AVP) to liver (AVP-V₁ site) and kidney (AVP-V₂site) tissue was determined using crude membrane preparations asdescribed previously [Pettibone, D. J., et al., J. Pharmacol. and Exper.Ther., 256(1): 304-308 (1991)]. Uterine tissue was taken fromnonpregnant adult Sprague-Dawley rats (Taconic Farms, Germantown, N.Y.)pretreated (18-24 h) with diethylstilbestrol propionate (DES; 300 μg/kg,i.p.). Uterine tissue (full thickness) was also taken with informedconsent from nonlabor pregnant women undergoing cesarean section at 38to 39 weeks gestation (Oregon Health Sciences Center, Portland, Or.).Liver and kidney medulla samples were taken from male rats and fromhuman surgical and early postmortem donors (National Disease ResearchInterchange, Philadelphia Pa.; Analytical Biological Services,Wilmington, De.).

Competition studies were conducted at equilibrium using 1 nM [³ H]OT or0.5 nM [³ H]AVP in the following buffer: 50 mM Tris, 5 mM MgCl₂, 0.1%bovine serum albumin. Nonspecific binding was determined using 1 μMunlabeled OT or AVP in their respective assays. The binding reactionswere initiated by the addition of tissue preparation and terminated byfiltration using a Skatron cell harvester (model 7019, Skatron, Inc.,Sterling, Va.). Ki values were calculated for each compound using threeto six separate IC₅₀ determinations (Ki=IC₅₀ /[1-c/K_(d) ]); [Cheng,Y-C; Prusoff, W. H.; Biochem. Pharmacol. 22:3099 (1973)] with mean K_(d)values obtained from replicate (n=3) equilibrium saturation bindingassays (10 point, 100 fold concentration range): [³ H]OT rat uterus,0.69 nM; human myometrium, 1.1 nM; [³ H]AVP: rat liver, 0.21 nM; ratkidney, 0.27 nM; human liver, 0.27 nM; human kidney, 1.4 nM. Computeranalysis of the saturation assays by EBDA/LIGAND [McPherson, G. A.:Kinetic, Ebda, Ligand, Lowry: A Collection of Radioligand BindingAnalysis Programs, Elsevier Science Publishers, Amsterdam (1985)]indicated that both radioligands apparently bound to single sites in alltissues examined. The final protein concentration for the varioustissues in each assay ranged from 150 to 300 μg/ml [Lowry, P. H.;Rosebrough, N. J.; Farr, A. L.; Randall, R. J.; J. Biol. Chem.,193:265-275 (1951)].

IC₅₀ values were determined for the [³ H]OT and [³ H]AVP binding assaysby linear regression of the relation log concentration of compound vs.percent inhibition of specific binding. Data is either reported as agiven percentage of inhibition at a specified concentration, or if anIC₅₀ was calculated, as a nanomolar concentration. Representativecompounds of the present invention were found to have IC₅₀ values foroxytocin in the range of 1-500 nM.

The oxytocin antagonistic effect of the compounds of the presentinvention can be further evaluated according to the in vitro and/or invitro functional assays described in detail in D. J. Pettibone et al.,Drug Devel. Res. 1993, 30, 129-142.

While the foregoing specification teaches the principles of the presentinvention, with examples for the purpose of illustration, it will beunderstood that the practice of the invention encompasses all of theusual variations, adaptions and/or modifications as come within thescope of the following claims and their equivalents.

What is claimed is:
 1. A compound of the formula I ##STR46## or apharmaceutically acceptable salt thereof wherein:Ar is unsubstituted,mono-, or disubstituted phenyl, naphthyl, pyridyl, pyrazinyl, orpyrimidyl, in which the substituents on carbon are independentlyselected from the group consisting of: C₁₋₅ alkyl, C₁₋₅ alkoxyl,halogen, nitro, cyano, and CF₃ ; R¹ is CON(R⁴)₂ ; R² is OCH₂ CF₃ ; R³ is##STR47## R⁴ is independently selected from the group consisting ofhydrogen and C₁₋₅ alkyl; and R⁷ is selected from the group consisting ofhydrogen, C₃₋₇ cycloalkyl substituted C₁₋₅ alkyl, SO₂ -C₁₋₅ alkyl,CO-C₁₋₅ alkyl, and hydroxy C₁₋₅ alkyl.
 2. A compound of claim 1whereinAr is mono-C₁₋₅ alkylsubstituted phenyl; R¹ is CONH₂ ; R² is OCH₂CF₃ ; and R3 is ##STR48##
 3. A compound of claim 2 of the Structure II:or pharmaceutically acceptable salts thereof.
 4. A compound of claim 1selected from the group consistingof:1-(4-(4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;1-(4-(N-cyclopropylmethyl-4-piperidinyloxy)-2-(2,2,2,-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;1-(4-(N-methylsulfonyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)-phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;1-(4-(N-acetyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenyl-acetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine;1-(4-(N-2-methyl-2-hydroxypropyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)-piperazine;or pharmaceutically acceptable salts thereof.
 5. A pharmaceuticalcomposition comprising the compound of claim 1 and a pharmaceuticallyacceptable carrier.
 6. A method of eliciting an oxytocin antagonizingeffect in a mammal in need thereof, comprising administering to themammal a therapeutically effective amount of the compound of claim
 1. 7.A method of treating preterm labor in a mammal in need thereof,comprising administering to the mammal a therapeutically effectiveamount of the compound of claim
 1. 8. A method of stopping laborpreparatory to caesarian delivery in a mammal in need thereof,comprising administering to the mammal a therapeutically effectiveamount of the compound of claim
 1. 9. A method of treating dysmenorrheain a mammal in need thereof, comprising administering to the mammal atherapeutically effective amount of the compound of claim
 1. 10. Amethod of increasing fertility and embryonic survival in a farm animal,comprising administering to the farm animal a therapeutically effectiveamount of the compound of claim
 1. 11. A method for improving survivalof a farm animal neonate comprising controlling timing of parturition toeffect delivery of the neonate during daylight hours by administering toa farm animal which is expected to deliver the neonate within 24 hours atherapeutically effective amount of the compound of claim
 1. 12. Amethod of controlling the timing of estrus in a farm animal, comprisingadministering to the farm animal a therapeutically effective amount ofthe compound of claim 1.